Validation of the NCCN/Yale criteria for the identification of pathogenic variant carriers.

Background: Diffuse gastric and lobular breast cancer (LBC) syndrome is an autosomal-dominant syndrome characterised by early-onset diffuse gastric cancer and LBC most often caused by germline pathogenic variants (PVs) in . We previously showed the International Gastric Cancer Linkage Consortium (IGCLC) criteria for genetic testing to have poor sensitivity for PV and proposed our own simpler and more sensitive Yale criteria. The European Reference Network on Genetic Tumour Risk Syndromes subsequently proposed expanding the IGCLC criteria and showed its LBC-expanded criteria to be more sensitive than the IGCLC criteria in a European cohort of PV carriers.

Germline Genetic Testing After Cancer Diagnosis.

Importance: Germline genetic testing is recommended by practice guidelines for patients diagnosed with cancer to enable genetically targeted treatment and identify relatives who may benefit from personalized cancer screening and prevention.

Objective: To describe the prevalence of germline genetic testing among patients diagnosed with cancer in California and Georgia between 2013 and 2019.

Design, Setting, And Participants: Observational study including patients aged 20 years or older who had been diagnosed with any type of cancer between January 1, 2013, and March 31, 2019, that was reported to statewide Surveillance, Epidemiology, and End Results registries in California and Georgia.

Functional and Clinical Characterization of Variants of Uncertain Significance Identifies a Hotspot for Inactivating Missense Variants in RAD51C.

Unlabelled: Pathogenic protein-truncating variants of RAD51C, which plays an integral role in promoting DNA damage repair, increase the risk of breast and ovarian cancer. A large number of RAD51C missense variants of uncertain significance (VUS) have been identified, but the effects of the majority of these variants on RAD51C function and cancer predisposition have not been established. Here, analysis of 173 missense variants by a homology-directed repair (HDR) assay in reconstituted RAD51C-/- cells identified 30 nonfunctional (deleterious) variants, including 18 in a hotspot within the ATP-binding region.

Fibroblast testing can inform medical management in individuals with mosaic variants detected on hereditary cancer panels.

Mosaic variants are regularly detected on hereditary cancer genetic tests. While some of these variants may be constitutional, the majority are likely limited to blood lineages. In the present study, we correlate clinical histories from individuals with mosaic findings identified on hereditary cancer testing and the outcomes of follow-up fibroblast (FB) testing.

Classification of BRCA2 Variants of Uncertain Significance (VUS) Using an ACMG/AMP Model Incorporating a Homology-Directed Repair (HDR) Functional Assay.

Purpose: The identification of variants of uncertain significance (VUS) in the BRCA1 and BRCA2 genes by hereditary cancer testing poses great challenges for the clinical management of variant carriers. The ACMG/AMP (American College of Medical Genetics and Genomics/Association for Molecular Pathology) variant classification framework, which incorporates multiple sources of evidence, has the potential to establish the clinical relevance of many VUS. We sought to classify the clinical relevance of 133 single-nucleotide substitution variants encoding missense variants in the DNA-binding domain (DBD) of BRCA2 by incorporating results from a validated functional assay into an ACMG/AMP-variant classification model from a hereditary cancer-testing laboratory.