vaRHC: an R package for semi-automation of variant classification in hereditary cancer genes according to ACMG/AMP and gene-specific ClinGen guidelines

Abstract

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.

Tumor analysis of MMR genes in Lynch‐like syndrome: Challenges associated with results interpretation

“…All variants identified in coding and adjacent intronic regions (i.e., ±20 bp) at variant allele frequencies (VAFs) ≥5% and covered at ≥30X were retrieved from the following genes: MLH1 (NM_000249.3), MLH3 (NM_001040108.1), MSH2 (NM_000251.1), MSH3 (NM_002439.3), MSH6 (NM_000179.2), MUTYH (NM_001128425.1), PMS2 (NM_000535.5), POLD1 (NM_001256849.1), and POLE (NM_006231.2). Variant classification was performed using vaRHC, an in‐house developed tool for the semi‐automation of variant interpretation according to ACMG/AMP ClinGen's gene‐specific guidelines 10 . Whenever possible, loss of heterozygosity (LOH) was assessed by comparing the allelic fraction of germline heterozygous SNPs in paired tumor DNA.…”

“…Variant classification was performed using vaRHC, an in‐house developed tool for the semi‐automation of variant interpretation according to ACMG/AMP ClinGen's gene‐specific guidelines. 10 Whenever possible, loss of heterozygosity (LOH) was assessed by comparing the allelic fraction of germline heterozygous SNPs in paired tumor DNA. LOH status was considered positive if at least three constitutionally heterozygous SNPs displayed an allelic imbalance in tumor tissue.…”

Tumor analysis of MMR genes in Lynch-like syndrome: challenges associated to results interpretation

“…±20 bp) at variant allele frequencies (VAFs) ≥ 5% and covered at ≥ 30X were retrieved from the following genes: MLH1 (NM_000249.3), MLH3 (NM_001040108.1), MSH2 (NM_000251.1), MSH3 (NM_002439.3), MSH6 (NM_000179.2), MUTYH (NM_001128425.1), PMS2 (NM_000535.5), POLD1 (NM_001256849.1) and POLE (NM_006231.2). Variant classi cation was performed using vaRHC, an inhouse developed tool for the semi-automation of variant interpretation according to ACMG/AMP and ClinGen's gene-speci c guidelines 11 . Whenever possible, loss of heterozygosity (LOH) was assessed in tumor DNA by analyzing the alternative allele ratio of germline heterozygous SNPs previously genotyped by Sanger sequencing or NGS in the routine clinical setting 12 .…”