Output

Interactive HTML report (flexdashboard)

An interactive and tier-structured HTML report (dashboard-like) that shows the most relevant findings in the query cancer genome has the following naming convention:

<sample_id>.pcgr_acmg.<genome_assembly>.flexdb.html

  • The sample_id is provided as input by the user, and reflects a unique identifier of the tumor-normal sample pair to be analyzed.

Interactive HTML report (rmarkdown)

An interactive and tier-structured HTML report that shows the most relevant findings in the query cancer genome has the following naming convention:

<sample_id>.pcgr_acmg.<genome_assembly>.html

  • The sample_id is provided as input by the user, and reflects a unique identifier of the tumor-normal sample pair to be analyzed.

The report is structured in seven main sections, described in more detail below:

  1. Report and query settings
    • Lists key configurations provided by user
  2. Main results
    • Nine value boxes that highlight the main properties of the tumor sample:
      1. Tumor purity - as provided by the user
      2. Tumor ploidy - as provided by the user
      3. Mutational signatures - two most prevalent signatures (other than aging)
      4. Tier 1 variants (top four)
      5. Tier 2 variants (top four)
      6. Tumor mutational burden (TMB)
      7. Microsatellite instability (MSI) status
      8. Somatic copy number aberrations of clinical significance
      9. Kataegis events
  3. Somatic SNVs/InDels
    • Tumor mutational burden (TMB)
      • given a coding target region size specified by the user (ideally the callable target size), an estimate of the mutational burden is provided
      • The estimated TMB is shown in the context of TMB distributions from different primary sites in TCGA
    • Tier & variant statistics
      • indicate total variant numbers across variant types, coding types and tiers
    • Global distribution - allelic support
      • distribution (histogram) of variant allelic support for somatic variants (will only be present in the report if specific fields in input VCF is defined and specified by the user)
    • Global variant browser
      • permits exploration of the whole SNV/InDel dataset by filtering along several dimensions (call confidence, variant sequencing depth/support, variant consequence etc.)
    • Tier tables
      • Variants are organized into five (tier 1-4 + noncoding) interactive datatables) according to clinical utility
      • Contents of the tier tables are outlined below
  4. Somatic CNAs
    • Segments - amplifications and homozygous deletions
      • Based on user-defined/default log-ratio thresholds of gains/losses, the whole CNA dataset can be navigated further through filters:
      • cytoband
      • type of CNA event - focal (less than 25% of chromosome arm affected) or broad
      • log ratio
    • Proto-oncogenes subject to copy number amplifications
      • Datatable listing known proto-oncogenes covered by user-defined/default amplifications and potential targeted therapies
    • Tumor suppressor genes subject to homozygous deletions
      • Datatable listing known tumor suppressor genes covered by user-defined/default losses and potential targeted therapies
    • Other drug targets subject to copy number aplifications
    • Copy number aberrations as biomarkers for prognosis, diagnosis, and drug response (both of strong significance and potential significance)
      • Interactive data table where the user can navigate aberrations acting as biomarkers across therapeutic contexts, tumor subtypes, evidence levels etc
  5. MSI status
    • Indicates predicted microsatellite stability from the somatic mutation profile and supporting evidence (details of the underlying MSI statistical classifier can be found here)
    • The MSI classifier was trained on TCGA exome samples.
  6. Mutational signatures
  7. Kataegis events
    • Detection of potential kataegis events using the algorithm outlined in the Kataegis Portal
  8. Germline findings
    • Main findings from CPSR report
  9. Clinial trials
    • Interactive table with annotated, molecularly targeted clinical trials from clinicaltrials.gov in the relevant tumor type
  10. Documentation
    • Annotation resources - software, databases and tools with version information
    • Report content
    • References - supporting scientific literature (key report elements)

Interactive datatables

The interactive datatables contain a number of hyperlinked annotations similar to those defined for the annotated VCF file, including the following:

  • SYMBOL - Gene symbol (Entrez/NCBI)
  • PROTEIN_CHANGE - Amino acid change (VEP)
  • CANCER_TYPE - Biomarker (tier 1/2): associated cancer type
  • EVIDENCE_LEVEL - Biomarker (tier 1/2): evidence level (A,B,C,D,E)
  • CLINICAL_SIGNIFICANCE - Biomarker (tier 1/2): drug sensitivity, poor/better outcome etc
  • EVIDENCE_TYPE - Biomarker (tier 1/2): predictive/diagnostic/therapeutic
  • DISEASE_ONTOLOGY_ID - Biomarker (tier 1/2): associated cancer type (Disease Ontology)
  • EVIDENCE_DIRECTION - Biomarker (tier 1/2): supports/does not support
  • DESCRIPTION - Biomarker (tier 1/2): description
  • VARIANT_ORIGIN - Biomarker (tier 1/2): variant origin (germline/somatic)
  • BIOMARKER_MAPPING - Biomarker (tier 1/2): accuracy of genomic mapping (exact,codon,exon)
  • CITATION - Biomarker (tier 1/2): supporting literature
  • THERAPEUTIC_CONTEXT - Biomarker (tier 1/2): associated drugs
  • RATING - Biomarker (tier 1/2): trust rating from 1 to 5 (CIVIC)
  • GENE_NAME - gene name description (Entrez/NCBI)
  • PROTEIN_DOMAIN - PFAM protein domain
  • PROTEIN_FEATURE - UniProt feature overlapping variant site
  • CDS_CHANGE - Coding sequence change
  • MUTATION_HOTSPOT - Known cancer mutation hotspot
  • MUTATION_HOTSPOT_CANCERTYPE - Hotspot-associated cancer types
  • TCGA_FREQUENCY - Frequency of variant in TCGA cohorts
  • ICGC_PCAWG_OCCURRENCE - Frequency of variant in ICGC-PCAWG cohorts
  • DOCM_LITERATURE - Literature links - DoCM
  • DOCM_DISEASE - Associated diseases - DoCM
  • OPENTARGETS_RANK - Strength (max across all phenotypes) of phenotype association according to the Open Targets Platform
  • OPENTARGETS_ASSOCIATIONS - Phenotype associations with the gene retrieved from the Open Targets Platform
  • INTOGEN_DRIVER_MUT - predicted driver mutation - IntOGen
  • CONSEQUENCE - VEP consequence (primary transcript)
  • HGVSc - from VEP
  • HGVSp - from VEP
  • NCBI_REFSEQ - Transcript accession ID(s) (NCBI RefSeq)
  • ONCOGENE - Predicted as proto-oncogene from CancerMine/NCG
  • CANCERGENE_SUPPORT - Links to underlying publications (CancerMine) that support oncogenic/tumor suppressive role of gene
  • TUMOR_SUPPRESSOR - Predicted as tumor suppressor gene from CancerMine/NCG
  • PREDICTED_EFFECT - Effect predictions from dbNSFP
  • VEP_ALL_CSQ - All VEP transcript block consequences
  • DBSNP - dbSNP rsID
  • COSMIC - Cosmic mutation IDs
  • CLINVAR - ClinVar variant origin and associated phenotypes
  • CANCER_ASSOCIATIONS - Gene-associated cancer types from DisGenet
  • TARGETED_DRUGS - Targeted drugs from Open Targets Platform /ChEMBL
  • KEGG_PATHWAY - Gene-associated pathways from KEGG
  • CALL_CONFIDENCE - Variant confidence (as set by user in input VCF)
  • DP_TUMOR - Variant sequencing depth in tumor (as set by user in input VCF)
  • AF_TUMOR - Variant allelic fraction in tumor (as set by user in input VCF)
  • DP_CONTROL - Variant sequencing depth in control sample (as set by user in input VCF)
  • AF_CONTROL - Variant allelic fraction in control sample (as set by user in input VCF)
  • GENOMIC_CHANGE - Variant ID
  • GENOME_VERSION - Genome assembly

Example reports:

DOI

The HTML reports have been tested using the following browsers:

  • Safari (Version 14.1.1 (16611.2.7.1.4))
  • Mozilla Firefox (83.0)
  • Google Chrome (Version 90.0.4430.212 (Official Build) (x86_64))

JSON

A compressed JSON file that stores all the essential content of the report is provided.

This file will easen the process of extracting particular parts of the report for further analysis or integration with other workflows. The JSON contains two main objects, metadata and content, where the former contains information about the settings, data versions, and the latter contains the various sections of the report.

Output files - somatic SNVs/InDels

Variant call format - VCF

A VCF file containing annotated, somatic calls (single nucleotide variants and insertion/deletions) is generated with the following naming convention:

<sample_id>.pcgr_acmg.<genome_assembly>.vcf.gz

Here, the sample_id is provided as input by the user, and reflects a unique identifier of the tumor-normal sample pair to be analyzed. Following common standards, the annotated VCF file is compressed with bgzip and indexed with tabix. Below follows a description of all annotations/tags present in the VCF INFO column after processing with the PCGR annotation pipeline:

VEP consequence annotations

  • CSQ - Complete consequence annotations from VEP. Format: Allele|Consequence|IMPACT|SYMBOL|Gene|Feature_type|Feature|BIOTYPE|EXON| INTRON|HGVSc|HGVSp|cDNA_position|CDS_position|Protein_position|Amino_acids| Codons|Existing_variation|ALLELE_NUM|DISTANCE|STRAND|FLAGS|PICK|VARIANT_CLASS| SYMBOL_SOURCE|HGNC_ID|CANONICAL|APPRIS|CCDS|ENSP|SWISSPROT|TREMBL|UNIPARC| RefSeq|DOMAINS|HGVS_OFFSET|AF|AFR_AF|AMR_AF|EAS_AF|EUR_AF|SAS_AF|gnomAD_AF| gnomAD_AFR_AF|gnomAD_AMR_AF|gnomAD_ASJ_AF|gnomAD_EAS_AF|gnomAD_FIN_AF| gnomAD_NFE_AF|gnomAD_OTH_AF|gnomAD_SAS_AF|CLIN_SIG|SOMATIC|PHENO| MOTIF_NAME|MOTIF_POS|HIGH_INF_POS|MOTIF_SCORE_CHANGE|TRANSCRIPTION_FACTORS|NearestExonJB
  • Consequence - Impact modifier for the consequence type (picked by VEP’s –flag_pick_allele option)
  • Gene - Ensembl stable ID of affected gene (picked by VEP’s –flag_pick_allele option)
  • Feature_type - Type of feature. Currently one of Transcript, RegulatoryFeature, MotifFeature (picked by VEP’s –flag_pick_allele option)
  • Feature - Ensembl stable ID of feature (picked by VEP’s –flag_pick_allele option)
  • cDNA_position - Relative position of base pair in cDNA sequence (picked by VEP’s –flag_pick_allele option)
  • CDS_position - Relative position of base pair in coding sequence (picked by VEP’s –flag_pick_allele option)
  • CDS_CHANGE - Coding, transcript-specific sequence annotation (picked by VEP’s –flag_pick_allele option)
  • AMINO_ACID_START - Protein position indicating absolute start of amino acid altered (fetched from Protein_position)
  • AMINO_ACID_END - Protein position indicating absolute end of amino acid altered (fetched from Protein_position)
  • Protein_position - Relative position of amino acid in protein (picked by VEP’s –flag_pick_allele option)
  • Amino_acids - Only given if the variant affects the protein-coding sequence (picked by VEP’s –flag_pick_allele option)
  • Codons - The alternative codons with the variant base in upper case (picked by VEP’s –flag_pick_allele option)
  • IMPACT - Impact modifier for the consequence type (picked by VEP’s –flag_pick_allele option)
  • VARIANT_CLASS - Sequence Ontology variant class (picked by VEP’s –flag_pick_allele option)
  • SYMBOL - Gene symbol (picked by VEP’s –flag_pick_allele option)
  • SYMBOL_ENTREZ - Official gene symbol as provided by NCBI’s Entrez gene
  • SYMBOL_SOURCE - The source of the gene symbol (picked by VEP’s –flag_pick_allele option)
  • STRAND - The DNA strand (1 or -1) on which the transcript/feature lies (picked by VEP’s –flag_pick_allele option)
  • ENSP - The Ensembl protein identifier of the affected transcript (picked by VEP’s –flag_pick_allele option)
  • FLAGS - Transcript quality flags: cds_start_NF: CDS 5’, incomplete cds_end_NF: CDS 3’ incomplete (picked by VEP’s –flag_pick_allele option)
  • SWISSPROT - Best match UniProtKB/Swiss-Prot accession of protein product (picked by VEP’s –flag_pick_allele option)
  • TREMBL - Best match UniProtKB/TrEMBL accession of protein product (picked by VEP’s –flag_pick_allele option)
  • UNIPARC - Best match UniParc accession of protein product (picked by VEP’s –flag_pick_allele option)
  • HGVSc - The HGVS coding sequence name (picked by VEP’s –flag_pick_allele option)
  • HGVSp - The HGVS protein sequence name (picked by VEP’s –flag_pick_allele option)
  • HGVSp_short - The HGVS protein sequence name, short version (picked by VEP’s –flag_pick_allele option)
  • HGVS_OFFSET - Indicates by how many bases the HGVS notations for this variant have been shifted (picked by VEP’s –flag_pick_allele option)
  • NearestExonJB - VEP plugin that finds nearest exon junction for a coding sequence variant. Format: Ensembl exon identifier+distanceto exon boundary+boundary type(start/end)+exon length
  • MOTIF_NAME - The source and identifier of a transcription factor binding profile aligned at this position (picked by VEP’s –flag_pick_allele option)
  • MOTIF_POS - The relative position of the variation in the aligned TFBP (picked by VEP’s –flag_pick_allele option)
  • HIGH_INF_POS - A flag indicating if the variant falls in a high information position of a transcription factor binding profile (TFBP) (picked by VEP’s –flag_pick_allele option)
  • MOTIF_SCORE_CHANGE - The difference in motif score of the reference and variant sequences for the TFBP (picked by VEP’s –flag_pick_allele option)
  • CELL_TYPE - List of cell types and classifications for regulatory feature (picked by VEP’s –flag_pick_allele option)
  • CANONICAL - A flag indicating if the transcript is denoted as the canonical transcript for this gene (picked by VEP’s –flag_pick_allele option)
  • CCDS - The CCDS identifier for this transcript, where applicable (picked by VEP’s –flag_pick_allele option)
  • INTRON - The intron number (out of total number) (picked by VEP’s –flag_pick_allele option)
  • EXON - The exon number (out of total number) (picked by VEP’s –flag_pick_allele option)
  • LAST_EXON - Logical indicator for last exon of transcript (picked by VEP’s –flag_pick_allele option)
  • LAST_INTRON - Logical indicator for last intron of transcript (picked by VEP’s –flag_pick_allele option)
  • INTRON_POSITION - Relative position of intron variant to nearest exon/intron junction (NearestExonJB VEP plugin)
  • EXON_POSITION - Relative position of exon variant to nearest intron/exon junction (NearestExonJB VEP plugin)
  • DISTANCE - Shortest distance from variant to transcript (picked by VEP’s –flag_pick_allele option)
  • BIOTYPE - Biotype of transcript or regulatory feature (picked by VEP’s –flag_pick_allele option)
  • TSL - Transcript support level (picked by VEP’s –flag_pick_allele option)>
  • PUBMED - PubMed ID(s) of publications that cite existing variant - VEP
  • PHENO - Indicates if existing variant is associated with a phenotype, disease or trait - VEP
  • GENE_PHENO - Indicates if overlapped gene is associated with a phenotype, disease or trait - VEP
  • ALLELE_NUM - Allele number from input; 0 is reference, 1 is first alternate etc - VEP
  • REFSEQ_MATCH - The RefSeq transcript match status; contains a number of flags indicating whether this RefSeq transcript matches the underlying reference sequence and/or an Ensembl transcript (picked by VEP’s –flag_pick_allele option)
  • PICK - Indicates if this block of consequence data was picked by VEP’s –flag_pick_allele option
  • VEP_ALL_CONSEQUENCE - All transcript consequences (Consequence:SYMBOL:Feature_type:Feature:BIOTYPE) - VEP
  • EXONIC_STATUS - Indicates if variant consequence type is ‘exonic’ or ‘nonexonic’. We here define ‘exonic’ as any variant with either of the following consequence:
    • stop_gained / stop_lost
    • start_lost
    • frameshift_variant
    • missense_variant
    • splice_donor_variant
    • splice_acceptor_variant
    • inframe_insertion / inframe_deletion
    • synonymous_variant
    • protein_altering
  • CODING_STATUS - Indicates if primary variant consequence type is ‘coding’ or ‘noncoding’ (wrt. protein-alteration). ‘coding’ variants are here defined as those with an ‘exonic’ status, with the exception of synonymous variants

Gene information

  • ENTREZ_ID - Entrez gene identifier
  • APPRIS - Principal isoform flags according to the APPRIS principal isoform database
  • MANE_SELECT - Indicating if the transcript is the MANE Select or MANE Plus Clinical transcript for the gene (picked by VEP’s –flag_pick_allele_gene option)
  • UNIPROT_ID - UniProt identifier
  • UNIPROT_ACC - UniProt accession(s)
  • ENSEMBL_GENE_ID - Ensembl gene identifier for VEP’s picked transcript (ENSGXXXXXXX)
  • ENSEMBL_TRANSCRIPT_ID - Ensembl transcript identifier for VEP’s picked transcript (ENSTXXXXXX)
  • ENSEMBL_PROTEIN_ID - Ensembl corresponding protein identifier for VEP’s picked transcript
  • REFSEQ_MRNA - Corresponding RefSeq transcript(s) identifier for VEP’s picked transcript (NM_XXXXX)
  • CORUM_ID - Associated protein complexes (identifiers) from CORUM
  • TUMOR_SUPPRESSOR - Indicates whether gene is predicted as a tumor suppressor gene, from Network of Cancer Genes (NCG) & the CancerMine text-mining resource
  • TUMOR_SUPPRESSOR_EVIDENCE - Underlying evidence for gene being a tumor suppressor. Format: NCG:<TRUE|FALSE>&CancerMine:<LC|MC|HC>:num_citations
  • ONCOGENE - Indicates whether gene is predicted as an oncogene, from Network of Cancer Genes (NCG) & the CancerMine text-mining resource
  • ONCOGENE_EVIDENCE - Underlying evidence for gene being an oncogene. Format: NCG:<TRUE|FALSE>&CancerMine:<LC|MC|HC>:num_citations
  • INTOGEN_DRIVER - Gene is predicted as a cancer driver in the IntoGen Cancer Drivers Database
  • TCGA_DRIVER - Gene is predicted as a cancer driver in the TCGA pan-cancer analysis of cancer driver genes and mutations
  • PROB_EXAC_LOF_INTOLERANT - dbNSFP_gene: the probability of being loss-of-function intolerant (intolerant of both heterozygous and homozygous lof variants) based on ExAC r0.3 data
  • PROB_EXAC_LOF_INTOLERANT_HOM - dbNSFP_gene: the probability of being intolerant of homozygous, but not heterozygous lof variants based on ExAC r0.3 data
  • PROB_EXAC_LOF_TOLERANT_NULL - dbNSFP_gene: the probability of being tolerant of both heterozygous and homozygous lof variants based on ExAC r0.3 data
  • PROB_EXAC_NONTCGA_LOF_INTOLERANT - dbNSFP_gene: the probability of being loss-of-function intolerant (intolerant of both heterozygous and homozygous lof variants) based on ExAC r0.3 nonTCGA subset
  • PROB_EXAC_NONTCGA_LOF_INTOLERANT_HOM - dbNSFP_gene: the probability of being intolerant of homozygous, but not heterozygous lof variants based on ExAC r0.3 nonTCGA subset
  • PROB_EXAC_NONTCGA_LOF_TOLERANT_NULL - dbNSFP_gene: the probability of being tolerant of both heterozygous and homozygous lof variants based on ExAC r0.3 nonTCGA subset
  • PROB_GNOMAD_LOF_INTOLERANT - dbNSFP_gene: the probability of being loss-of-function intolerant (intolerant of both heterozygous and homozygous lof variants based on gnomAD 2.1 data
  • PROB_GNOMAD_LOF_INTOLERANT_HOM - dbNSFP_gene: the probability of being intolerant of homozygous, but not heterozygous lof variants based on gnomAD 2.1 data
  • PROB_GNOMAD_LOF_TOLERANT_NULL - dbNSFP_gene: the probability of being tolerant of both heterozygous and homozygous lof variants based on gnomAD 2.1 data
  • PROB_HAPLOINSUFFICIENCY - dbNSFP_gene: Estimated probability of haploinsufficiency of the gene (from http://dx.doi.org/10.1371/journal.pgen.1001154)
  • ESSENTIAL_GENE_CRISPR - dbNSFP_gene: Essential (E) or Non-essential phenotype-changing (N) based on large scale CRISPR experiments. from http://dx.doi.org/10.1126/science.aac7041
  • ESSENTIAL_GENE_CRISPR2 - dbNSFP_gene: Essential (E), context-Specific essential (S), or Non-essential phenotype-changing (N) based on large scale CRISPR experiments. from http://dx.doi.org/10.1016/j.cell.2015.11.015

Variant effect and protein-coding information

  • MUTATION_HOTSPOT - mutation hotspot codon in cancerhotspots.org. Format: gene_symbol | codon | q-value
  • MUTATION_HOTSPOT_TRANSCRIPT - hotspot-associated transcripts (Ensembl transcript ID)
  • MUTATION_HOTSPOT_CANCERTYPE - hotspot-associated cancer types (from cancerhotspots.org)
  • UNIPROT_FEATURE - Overlapping protein annotations from UniProt KB
  • PFAM_DOMAIN - Pfam domain identifier (from VEP)
  • INTOGEN_DRIVER_MUT - Indicates if existing variant is predicted as driver mutation from IntoGen Catalog of Driver Mutations
  • PUTATIVE_DRIVER_MUTATION - Variant is predicted as driver mutation in the TCGA pan-cancer analysis of cancer driver genes and mutations
  • EFFECT_PREDICTIONS - All predictions of effect of variant on protein function and pre-mRNA splicing from database of non-synonymous functional predictions - dbNSFP v4.2. Predicted effects are provided by different sources/algorithms (separated by ‘&’), T = Tolerated, N = Neutral, D = Damaging:
    1. SIFT
    2. MutationTaster (data release Nov 2015)
    3. MutationAssessor (release 3)
    4. FATHMM (v2.3)
    5. PROVEAN (v1.1 Jan 2015)
    6. FATHMM_MKL
    7. PRIMATEAI
    8. DEOGEN2
    9. DBNSFP_CONSENSUS_RNN (Ensembl/consensus prediction, based on deep learning)
    10. SPLICE_SITE_EFFECT_ADA (Ensembl/consensus prediction of splice-altering SNVs, based on adaptive boosting)
    11. SPLICE_SITE_EFFECT_RF (Ensembl/consensus prediction of splice-altering SNVs, based on random forest)
    12. M-CAP
    13. MutPred
    14. GERP
    15. BayesDel
    16. LIST-S2
    17. ALoFT
  • DBNSFP_BAYESDEL_ADDAF - predicted effect from BayesDel (dbNSFP)
  • DBNSFP_LIST_S2 - predicted effect from LIST-S2 (dbNSFP)
  • DBNSFP_SIFT - predicted effect from SIFT (dbNSFP)
  • DBNSFP_PROVEAN - predicted effect from PROVEAN (dbNSFP)
  • DBNSFP_MUTATIONTASTER - predicted effect from MUTATIONTASTER (dbNSFP)
  • DBNSFP_MUTATIONASSESSOR - predicted effect from MUTATIONASSESSOR (dbNSFP)
  • DBNSFP_M_CAP - predicted effect from M-CAP (dbNSFP)
  • DBNSFP_ALOFTPRED - predicted effect from ALoFT (dbNSFP)
  • DBNSFP_MUTPRED - score from MUTPRED (dbNSFP)
  • DBNSFP_FATHMM - predicted effect from FATHMM (dbNSFP)
  • DBNSFP_PRIMATEAI - predicted effect from PRIMATEAI (dbNSFP)
  • DBNSFP_DEOGEN2 - predicted effect from DEOGEN2 (dbNSFP)
  • DBNSFP_GERP - evolutionary constraint measure from GERP (dbNSFP)
  • DBNSFP_FATHMM_MKL - predicted effect from FATHMM-mkl (dbNSFP)
  • DBNSFP_META_RNN - predicted effect from ensemble prediction (deep learning - dbNSFP)
  • DBNSFP_SPLICE_SITE_RF - predicted effect of splice site disruption, using random forest (dbscSNV)
  • DBNSFP_SPLICE_SITE_ADA - predicted effect of splice site disruption, using boosting (dbscSNV)

Variant frequencies/annotations in germline/somatic databases

Clinical associations

  • CLINVAR_MSID - ClinVar Measure Set/Variant ID
  • CLINVAR_ALLELE_ID - ClinVar allele ID
  • CLINVAR_PMID - Associated Pubmed IDs for variant in ClinVar - germline state-of-origin
  • CLINVAR_HGVSP - Protein variant expression using HGVS nomenclature
  • CLINVAR_PMID_SOMATIC - Associated Pubmed IDs for variant in ClinVar - somatic state-of-origin
  • CLINVAR_CLNSIG - Clinical significance for variant in ClinVar - germline state-of-origin
  • CLINVAR_CLNSIG_SOMATIC - Clinical significance for variant in ClinVar - somatic state-of-origin
  • CLINVAR_MEDGEN_CUI - Associated MedGen concept identifiers (CUIs) - germline state-of-origin
  • CLINVAR_MEDGEN_CUI_SOMATIC - Associated MedGen concept identifiers (CUIs) - somatic state-of-origin
  • CLINVAR_VARIANT_ORIGIN - Origin of variant (somatic, germline, de novo etc.) for variant in ClinVar
  • CLINVAR_REVIEW_STATUS_STARS - Rating of the ClinVar variant (0-4 stars) with respect to level of review
  • DOCM_PMID - Associated Pubmed IDs for variant in Database of Curated Mutations
  • OPENTARGETS_DISEASE_ASSOCS - Associations between protein targets and disease based on multiple lines of evidence (mutations,affected pathways,GWAS, literature etc). Format: CUI:EFO_ID:IS_DIRECT:OVERALL_SCORE
  • OPENTARGETS_TRACTABILITY_COMPOUND - Confidence for the existence of a modulator (small molecule) that interacts with the target to elicit a desired biological effect
  • OPENTARGETS_TRACTABILITY_ANTIBODY - Confidence for the existence of a modulator (antibody) that interacts with the target to elicit a desired biological effect

Other

Tab-separated values (TSV)

Annotated List of all SNVs/InDels

We provide a tab-separated values file with most important annotations for SNVs/InDels. The file has the following naming convention:

<sample_id>.pcgr_acmg.<genome_assembly>.snvs_indels.tiers.tsv

The SNVs/InDels are organized into different tiers (as defined above for the HTML report)

The following variables are included in the tiered TSV file:

1. CHROM - Chromosome
2. POS - Position (VCF-based)
3. REF - Reference allele
4. ALT - Alternate allele
5. GENOMIC_CHANGE - Identifier for variant at the genome (VCF) level, e.g. 1:g.152382569A>G
      Format: (<chrom>:g.<position><ref_allele>><alt_allele>)
6. GENOME_VERSION - Assembly version, e.g. GRCh37
7. VCF_SAMPLE_ID - Sample identifier
8. VARIANT_CLASS - Variant type, e.g. SNV/insertion/deletion
9. SYMBOL - Gene symbol
10. GENE_NAME - Gene description
11. CCDS - CCDS identifier
12. CANONICAL - indication of canonical transcript
13. ENTREZ_ID - Entrez gene identifier
14. UNIPROT_ID - UniProt protein identifier
15. ENSEMBL_TRANSCRIPT_ID - Ensembl transcript identifier
16. ENSEMBL_GENE_ID - Ensembl gene identifier
17. REFSEQ_MRNA - RefSeq mRNA identifier
18. REFSEQ_PEPTIDE - RefSeq peptide identifier
19. TRANSCRIPT_MANE_SELECT - MANE select transcript identifier
20. ONCOGENE - Gene is predicted/classified as an oncogene (CancerMine/NCG)
21. TUMOR_SUPPRESSOR - Gene is predicted/classified as tumor suppressor (CancerMine/NCG)
22. ONCOGENE_EVIDENCE - Underlying evidence for oncogene prediction/classification
23. TUMOR_SUPPRESSOR_EVIDENCE - Underlying evidence for tumor suppressor prediction/classification
24. CONSEQUENCE - Variant consequence (as defined above for VCF output:
    Consequence)
25. PROTEIN_CHANGE - Protein change (HGVSp without reference accession)
26. PROTEIN_DOMAIN - Protein domain description (Pfam)
27. CODING_STATUS - Coding variant status wrt. protein alteration ('coding' or 'noncoding')
28. EXONIC_STATUS - Exonic variant status ('exonic' or 'nonexonic')
29. CDS_CHANGE - composite VEP-based variable for coding change, format:
    Consequence:Feature:cDNA_position:EXON:HGVSp_short
30. HGVSp
31. HGVSc
32. REGULATORY_ANNOTATION - Regulatory annotations (promoter/enhancer/TF_binding site overlap etc.) from VEP (optional)
33. EFFECT_PREDICTIONS - as defined above for VCF
34. MUTATION_HOTSPOT - mutation hotspot codon in
    cancerhotspots.org. Format: gene_symbol | codon | q-value
35. MUTATION_HOTSPOT_TRANSCRIPT - hotspot-associated transcripts (Ensembl transcript ID)
36. MUTATION_HOTSPOT_CANCERTYPE - hotspot-associated cancer types (from cancerhotspots.org)
37. PUTATIVE_DRIVER_MUTATION - Indicates if variant is predicted as
    driver mutation from TCGA's PanCancer study of cancer driver mutation
38. CHASMPLUS_DRIVER - Driver mutation predicted by CHASMplus algorithm
39. CHASMPLUS_TTYPE - Tumor type for which mutation is predicted as driver by CHASMplus
40. VEP_ALL_CSQ - all VEP transcript block consequences
41. DBSNPRSID - dbSNP reference cluster ID
42. COSMIC_MUTATION_ID - COSMIC mutation ID
43. TCGA_PANCANCER_COUNT - Raw variant count across all TCGA tumor types
44. TCGA_FREQUENCY - Frequency of variant across TCGA tumor types. Format: tumortype|
percent affected|affected cases|total cases
45. ICGC_PCAWG_OCCURRENCE - Mutation occurrence in ICGC-PCAWG by project:
project_code|affected_donors|tested_donors|frequency
46. CHEMBL_COMPOUND_ID - Compounds (as ChEMBL IDs) that are targeted towards the encoded protein (from Open Targets Platform)
47. CHEMBL_COMPOUND_TERMS - Compounds (as drug names) that are targeted towards the encoded protein (from Open Targets Platform)
48. SIMPLEREPEATS_HIT - Variant overlaps UCSC _simpleRepeat_ sequence repeat track
49. WINMASKER_HIT - Variant overlaps UCSC _windowmaskerSdust_ sequence repeat track
50. OPENTARGETS_RANK - OpenTargets association score (between 0 and 1) for gene (maximum across cancer phenotypes)
51. CLINVAR - ClinVar association: variant origin and associated traits
52. CLINVAR_CLNSIG - clinical significance of ClinVar variant
53. GLOBAL_AF_GNOMAD - global germline allele frequency in gnomAD
54. GLOBAL_AF_1KG - 1000G Project - phase 3, germline allele frequency
55. NCER_PERCENTILE - Genome-wide percentile score (10bp bins) from the non-coding Essential Regulation (ncER) algorithm
56. CALL_CONFIDENCE - confidence indicator for somatic variant
57. DP_TUMOR - sequencing depth at variant site (tumor sample)
58. AF_TUMOR - allelic fraction of alternate allele (tumor sample)
59. DP_CONTROL - sequencing depth at variant site (control sample)
60. AF_CONTROL - allelic fraction of alternate allele (control sample)
61. TIER
62. TIER_DESCRIPTION

NOTE: The user has the possibility to append the TSV file with data from other tags in the input VCF of interest (i.e. using the custom_tags option in the TOML configuration file)

Mutational signature contributions

We provide a tab-separated values file information about mutational signatures detected in the tumor sample. The file has the following naming convention:

<sample_id>.pcgr_acmg.<genome_assembly>.mutational_signatures.tsv

The format of the TSV file is the following:

1. signature_id - identifier for signature
2. sample_id - sample identifier
3. prop_signature - relative contribution of mutational signature
4. group - keyword for signature aetiology
5. all_reference_signatures - logical indicating if all reference signatures were used for reconstruction/inference
6. tumor_type - tumor type (used for retrieval of reference signatures)
7. reference_collection - collection used for reference signatures
8. reference_signatures - signatures present in reference collection
9. fitting_accuracy - accuracy of mutational signature fitting

Output files - somatic copy number aberrations

1. Tab-separated values (TSV)

Copy number segments are intersected with the genomic coordinates of all transcripts from GENCODE’s basic gene annotation. In addition, PCGR attaches cancer-relevant annotations for the affected transcripts. The naming convention of the compressed TSV file is as follows:

<sample_id>.pcgr_acmg.<genome_assembly>.cna_segments.tsv.gz

NOTE: This is file is organized according to the affected transcripts (i.e. one line/record per affected transcript).

The format of the compressed TSV file is the following:

1. chrom - chromosome
2. segment_start - start of copy number segment
3. segment_end - end of copy number segment
4. segment_id - segment identifier
5. segment_length_Mb - length of segment in Mb
6. event_type - focal or broad (covering more than 25% of chromosome arm)
7. cytoband(s) - cytobands covered by segment
8. LogR - Copy log-ratio
9. sample_id - Sample identifier
10. ensembl_gene_id
11. symbol - gene symbol
12. ensembl_transcript_id
13. transcript_start - chromosomal position of transcript start
14. transcript_end - chromosomal position of transcript end
15. transcript_overlap_percent - percent of transcript length covered by CN segment
16. name - gene name description
17. biotype - type of gene
18. tumor_suppressor - tumor suppressor gene status (CancerMine literature database/Network of Cancer Genes)
19. oncogene - oncogene status (CancerMine literature database/Network of Cancer Genes)
20. intogen_drivers - predicted driver gene status (IntoGen Cancer Drivers Database)
21. chembl_compound_id - anti-cancer drugs that are targeted towards the encoded protein (from Open Targets Platform, drugs are listed as ChEMBL compound identifiers)
22. gencode_tag
23. gencode_release