VarSome Clinical is a CE IVDR-certified, HIPAA-compliant platform for interpreting NGS data. It supports analysis of genomes, exomes, and gene panels from individual samples, trios, families, or cohorts.

The platform accepts both FASTQ and VCF files. FASTQ inputs must come from Illumina, MGI, or Element Biosciences sequencers. VCFs can be uploaded from any platform that conforms to the standard specification.

Shared Features of Germline and Somatic Pipelines

VarSome Clinical supports genome-wide analyses with pipelines optimised for reproducibility, sensitivity, and precision. The platform integrates over 140 public and proprietary datasets, representing more than 33 billion data points, with updates regularly incorporated to reflect current knowledge.

Variant filtering is flexible and user-friendly. Users can apply dynamic filters based on frequency, pathogenicity, zygosity, or gene lists, and use more advanced algorithmic filters for inheritance analysis, candidate gene prioritisation, or variant detection based on functional context.

Reports are fully customisable, with support for editable templates, institutional branding, literature references, and user-added comments. Templates can be linked to specific workflows for germline or somatic analysis.

Users can compare current and historical samples, annotate variants with internal comments or classifications, and share findings within their institution or with approved partners. All user actions are logged for audit purposes, and each analysis includes a detailed quality control report covering alignment, variant calling, and classification metrics.

The platform supports FASTQ uploads via direct integration with Illumina BaseSpace and offers a robust API for automated data transfer and pipeline execution. Users also benefit from a global network of clinical geneticists who contribute curated interpretations, helping refine classifications and improve variant-level insight across the platform.

Germline Pipeline

For germline samples sequenced using hybridization-based capture kits, VarSome Clinical utilizes Sentieon's DNA Scope variant caller. This caller performs an improved version of GATK Haplotype variant calling. For amplicon kits on germline samples, VarDict is used.

Quality Filters for Germline Analyses (Capture Kit Samples):

• Coverage: Variants with fewer than 8 reads are marked as FAIL due to insufficient coverage.
• Quality (QUAL): For single-sample analyses, variants with a QUAL lower than 100 are assigned a FAIL call status. QUAL is the Phred-scaled probability that a REF/ALT polymorphism exists at the site.
• Genotype Quality (GQ): For multi-sample analyses (couple, family trio, or generic multi-sample), variants with a GQ lower than 20 are marked as FAIL. GQ represents the Phred-scaled confidence that the genotype assignment is correct. If a variant has a low GQ in one sample of a trio, it will be marked "Failed/Not genotyped" for that sample, but may pass in others.

Quality Filters for Germline Analyses (Amplicon Kit Samples):

• Allelic Balance (AB) cutoff: Set to 0.2. This rule applies to positions covered by more than 100 reads. Otherwise, a variant is reported only if AB is less than 20/coverage depth (meaning it's supported by at least 20 reads).

Germline Variant Classification

Germline variants are classified using ACMG guidelines, with each rule documented and explained. Users can manually adjust rules with supporting evidence. Classifications include: Benign, Likely Benign, VUS, Likely Pathogenic, and Pathogenic.

Somatic Pipeline

For somatic samples, VarSome Clinical uses Sentieon's TNhaplotyper2 algorithm for capture kit samples. This variant caller is designed to behave similarly to GATK’s Mutect2 and applies associated filtering tools. For amplicon kits on somatic samples, VarDict is used.

Quality Filters for Somatic Analyses (Capture Kit Samples):

Tnhaplotyper2 applies specific filters that either mark a variant as FAIL or do not.

• Filters that mark a variant as FAIL: map_qual, base_qual, contamination, weak_evidence, low_allele_frac, normal_artifact, panel_of_normals, strand_bias.
• Filters that do not mark a variant as FAIL: clustered_events, duplicate, fragment, multiallelic, n_ratio, orientation, position, slippage, haplotype, germline, strict_strand.

Quality Filters for Somatic Analyses (Amplicon Kit Samples):

• Allelic Balance (AB) cutoff: Set to 0.005. This rule applies to positions covered by more than 400 reads. Otherwise, a variant is reported only if AB is less than 20/coverage depth (meaning it's supported by at least 20 reads).

Somatic Variant Classification

Somatic variants are classified according to AMP (Association for Molecular Pathology) guidelines, using a four-tier system: Tier 1 (strong clinical significance), Tier 2 (potential clinical significance), Tier 3 (unknown significance), and Tier 4 (likely benign or benign). Classifications are based on factors such as therapeutic relevance, diagnostic impact, and supporting evidence from databases or literature.

VarSome Clinical supports AMP-based classification with integrated annotations from OncoKB™. Additional biomarkers, including tumour mutational burden (TMB) and microsatellite instability (MSI), are also included where available, helping to contextualise variant impact in oncology-focused analyses.

Summary

VarSome Clinical provides a single environment for germline and somatic variant interpretation, combining high-throughput pipelines with clear classification logic, flexible filtering, and full traceability. The platform supports both individual casework and high-volume workflows while allowing users to customize interpretation based on laboratory context.

To explore the platform in more detail or request a demo, visit docs.varsome.com or get in touch with our team.