Recommendations for risk allele evidence curation, classification, and reporting from the ClinGen Low Penetrance/Risk Allele Working Group.

Purpose: Genetic variants at the low end of the penetrance spectrum have historically been challenging to interpret because their high population frequencies exceed the disease prevalence of the associated condition, leading to a lack of clear segregation between the variant and disease. There is currently substantial variation in the classification of these variants, and no formal classification framework has been widely adopted. The Clinical Genome Resource Low Penetrance/Risk Allele Working Group was formed to address these challenges and promote harmonization within the clinical community.

Suspected clonal hematopoiesis as a natural functional assay of TP53 germline variant pathogenicity.

Purpose: Some variants identified by multigene panel testing of DNA from blood present with low variant allele fraction (VAF), often a manifestation of clonal hematopoiesis. Research has shown that the proportion of variants with low VAF is especially high in TP53, the Li-Fraumeni syndrome gene. Based on the hypothesis that variants with low VAF are positively selected as drivers of clonal hematopoiesis, we investigated the use of VAF as a predictor of TP53 germline variant pathogenicity.

Closing the gap: Systematic integration of multiplexed functional data resolves variants of uncertain significance in BRCA1, TP53, and PTEN.

Clinical interpretation of missense variants is challenging because the majority identified by genetic testing are rare and their functional effects are unknown. Consequently, most variants are of uncertain significance and cannot be used for clinical diagnosis or management. Although not much can be done to ameliorate variant rarity, multiplexed assays of variant effect (MAVEs), where thousands of single-nucleotide variant effects are simultaneously measured experimentally, provide functional evidence that can help resolve variants of unknown significance (VUSs).

An updated quantitative model to classify missense variants in the TP53 gene: A novel multifactorial strategy.

Multigene panel testing has led to an increase in the number of variants of uncertain significance identified in the TP53 gene, associated with Li-Fraumeni syndrome. We previously developed a quantitative model for predicting the pathogenicity of P53 missense variants based on the combination of calibrated bioinformatic information and somatic to germline ratio. Here, we extended this quantitative model for the classification of P53 predicted missense variants by adding new pieces of evidence (personal and family history parameters, loss-of-function results, population allele frequency, healthy individual status by age 60, and breast tumor pathology).

Specifications of the ACMG/AMP variant interpretation guidelines for germline TP53 variants.

Germline pathogenic variants in TP53 are associated with Li-Fraumeni syndrome, a cancer predisposition disorder inherited in an autosomal dominant pattern associated with a high risk of malignancy, including early-onset breast cancers, sarcomas, adrenocortical carcinomas, and brain tumors. Intense cancer surveillance for individuals with TP53 germline pathogenic variants is associated with reduced cancer-related mortality. Accurate and consistent classification of germline variants across clinical and research laboratories is important to ensure appropriate cancer surveillance recommendations.

Genotype-phenotype correlations among TP53 carriers: Literature review and analysis of probands undergoing multi-gene panel testing and single-gene testing.

Pathogenic germline variants in the TP53 gene predispose to a wide range of cancers, known collectively as Li-Fraumeni syndrome (LFS). There has been much research aimed to identify genotype-phenotype correlations, that is, differences between variant location and/or effect and cancer spectrum. These correlations, should they exist, have potential to impact clinical management of carriers.

A Rare Mutation Predominant in Ashkenazi Jews Confers Risk of Multiple Cancers.

Germline mutations in cause a rare high penetrance cancer syndrome, Li-Fraumeni syndrome (LFS). Here, we identified a rare tetramerization domain missense mutation, c.1000G>C;p.

Suggested application of HER2+ breast tumor phenotype for germline TP53 variant classification within ACMG/AMP guidelines.

Early onset breast cancer is the most common malignancy in women with Li-Fraumeni syndrome, caused by germline TP53 pathogenic variants. It has repeatedly been suggested that breast tumors from TP53 carriers are more likely to be HER2+ than those of noncarriers, but this information has not been incorporated into variant interpretation models for TP53. Breast tumor pathology is already being used quantitatively for assessing pathogenicity of germline variants in other genes, and it has been suggested that this type of evidence can be incorporated into current American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines for germline variant classification.

Differences in patient ascertainment affect the use of gene-specified ACMG/AMP phenotype-related variant classification criteria: Evidence for TP53.

The American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines for variant classification are widely used for clinical interpretation of gene test results. These guidelines may be specified to genes/syndromes of interest to improve their utility in the clinical setting. As part of these specifications, phenotype-related criteria can be detailed and weighted depending on the personal history of disease for a given variant carrier.

Assessment of Diagnostic Outcomes of RNA Genetic Testing for Hereditary Cancer.

Importance: Performing DNA genetic testing (DGT) for hereditary cancer genes is now a well-accepted clinical practice; however, the interpretation of DNA variation remains a challenge for laboratories and clinicians. Adding RNA genetic testing (RGT) enhances DGT by clarifying the clinical actionability of hereditary cancer gene variants, thus improving clinicians' ability to accurately apply strategies for cancer risk reduction and treatment.

Objective: To evaluate whether RGT is associated with improvement in the diagnostic outcome of DGT and in the delivery of personalized cancer risk management for patients with hereditary cancer predisposition.

p53 major hotspot variants are associated with poorer prognostic features in hereditary cancer patients.

TP53 pathogenic germline variation is associated with the multi-cancer predisposition Li-Fraumeni syndrome (LFS). Next-generation sequencing and multigene panel testing are highlighting variability in the clinical presentation of patients with TP53 positive results. We aimed to investigate if the p53 variants considered as major hotspots at both germline and somatic levels (p.

Genotype-phenotype associations among panel-based TP53+ subjects.

Purpose: Panel testing has led to the identification of TP53 pathogenic/likely pathogenic (P/LP) variant carriers (TP53+) who exhibit a broad range of phenotypes. We sought to evaluate and compare genotype-phenotype associations among TP53+ panel-ascertained subjects.

Methods: Between 2012 and 2017, 317 TP53+ subjects (279 females and 38 males) identified through panel testing at one testing laboratory were found to have evaluable clinical histories and molecular results.