Defects in DNA repair genes have been extensively associated with cancer susceptibility. Germline pathogenic variants (GPV) in genes involved in homologous recombination repair pathways predispose to cancers arising mainly in the breast and ovary, but also other tissues. The RAD51 paralogs RAD51C and RAD51D were included in this group 10 years ago when germline variants were associated with non-BRCA1/2 familial ovarian cancer. Here, we have reviewed the landscape of RAD51C and RAD51D germline variants in cancer reported in the literature during the last decade, integrating this list with variants identified by in-house patient screening. A comprehensive catalog of 341 variants that have been classified applying ACMG/AMP criteria has been generated pinpointing the existence of recurrent variants in both genes. Recurrent variants have been extensively discussed compiling data on population frequencies and functional characterization if available, highlighting variants that have not been fully characterized yet to properly establish their pathogenicity. Finally, we have complemented this data with relevant information regarding the conservation of mutated residues among RAD51 paralogs and modeling of putative hotspot areas, which contributes to generating an exhaustive update on these two cancer predisposition genes.

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Motivation Germline variant classification allows accurate genetic diagnosis and risk assessment. However, it is a tedious iterative process integrating information from several sources and types of evidence. It should follow gene-specific (if available) or general updated international guidelines. Thus, it is the main burden of the incorporation of NGS into the clinical setting. Results We created the vaRHC R package to assist the process of variant classification in hereditary cancer by : 1) collecting information from diverse databases; 2) assigning or denying different types of evidence according to updated ACMG/AMP gene-specific criteria for ATM, CDH1, CHEK2, MLH1, MSH2, MSH6, PMS2, PTEN, and TP53 and general criteria for other genes; 3) providing an automated classification of variants using a Bayesian metastructure and considering CanVIG-UK recommendations; 4) optionally printing the output to an .xlsx file. A validation using 659 classified variants demonstrated the robustness of vaRHC, presenting a better criteria assignment than Cancer SIGVAR, an available similar tool. Availability The source code can be consulted in the GitHub repository (https://github.com/emunte/vaRHC) Additionally, it will be submitted to CRAN soon. Supplementary information Supplementary data are available at Bioinformatics online.

BackgroundSchwannomatosis is a disorder characterized by a predisposition to multiple benign spinal, peripheral and intracranial nerve sheath tumors (schwannomas (SWNs)). The molecular mechanism of schwannomatosis involves several genes located on chromosome 22q, SMARCB1, LZTR1, NF2 and more recently, DGCR8. Case Presentation:here, we present a family with SMARCA4-associated schwannomatosis -this is the rst report of this association. The proband presented with a spinal SWN at age 30y whilst her mother (deceased) had had 4 peripheral SWNs (right and left arms) at age 50y followed by a glioblastoma (GBM) at age 54y. All the tumors, except for the GBM, showed loss of BRG1 (SMARCA4) in 80-90% of cells and loss of INI1 (SMARCB1) in the complementary 10-20% of cells. The GBM showed retention of BRG1 and INI1. Whole exome sequencing of the proband's germline revealed a likely pathogenic (LP) variant, SMARCA4 (NM_001128844.2):c.1752_1755del, p.(Lys585Argfs*27) (ClinVar ID: 873514). Furthermore, we identi ed LOH at the SMARCA4 locus along with 12-23 Mb of chromosome 19p in all SWNs (acting as the second hits), but not in the GBM. No other pathogenic variants or allelic imbalance on Chromosome 22q were detected in the schwannomas. Additionally, from DNA methylation analyses, we observed that the SMARCA4associated SWNs clustered together with other SWNs (mutated in SMARCB1 or LZTR1, or negative germline status) and away from rhabdoid tumours associated with SMARCA4 and SMARCB1 de ciency (small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) and atypical teratoid rhabdoid tumour (ATRT)). ConclusionTaken together, our ndings lead us to propose SMARCA4 as a new candidate schwannomatosis gene and that there might be other mechanisms by which SWNs are formed.