Welcome to HerediVar
Herzlich Willkommen auf der Homepage des HerediVar-Projekts des Deutschen Konsortiums Familiärer Brust- und Eierstockkrebs!
Das Deutsche Konsortium Familiärer Brust- und Eierstockkrebs (DK-FBREK) ist ein deutschlandweiter Verbund von universitären Zentren, mit dem Ziel Ratsuchende bzw.
Patientinnen mit einer familiären Belastung für Brustkrebs und Eierstockkrebs bundesweit optimal zu betreuen. Weitere Informationen zum Konsortium erhalten sie
auf unserer Homepage unter
DK-FBREK
.
Voraussetzung für die bestmögliche Berechnung des persönlichen Risikos für erblich bedingten Brust- und Eierstockkrebs als Voraussetzung für risikoadaptierte
Präventionsmaßnahmen und gezielte Therapien im Krankheitsfall ist die eindeutige Klassifikation der im Rahmen der Gendiagnostik identifizierten genetischen Varianten.
Eine große Herausforderung stellt dabei die große Zahl der mittels Next-Generation Sequencing (NGS)-basierten Genpanel-Untersuchungen detektierten Keimbahnvarianten
mit unklarer Signifikanz (VUS) dar. Dies sind genetische Veränderungen, deren Bedeutung für die Genfunktion und damit die mögliche Ursache der Erkrankung bisher
nicht geklärt ist. Denn viele Genvarianten sind Normvarianten, sog. Polymorphismen, d.h. sie beeinflussen die Funktion des Gens nicht.
Um dieser Herausforderung zu begegnen hat das DK-FBREK seit mehr als 10 Jahren eine Arbeitsgruppe (VUS-Task-Force) etabliert, welche die Klassifizierung der von den
Zentren des Konsortiums in die zentrale Datenbank gemeldeten Varianten überprüft und sich um die Klassifizierung von VUS bemüht. Des Weiteren wurden eigene
genspezifische Richtlinien für die Variantenklassifizierung auf Grundlage der Richtlinien internationaler Expertengremien entwickelt (IARC, ENIGMA, ClinGen). Diese
sind in den Publikationen auf
pubmed
und im
thieme verlag
zu finden.
Mitglieder des Expertengremiums arbeiten in den internationalen Arbeitsgruppen dieser Konsortien an der Anpassung und Weiterentwicklung der Bewertungsrichtlinien
mit. (
ENIGMA
,
ClinGen
)
Mittlerweile entsenden alle 23 Zentren des Konsortiums Mitglieder in die VUS-Task-Force, dennoch ist die Anzahl der gemeldeten Varianten und insbesondere VUS so
hoch, dass eine händische Bearbeitung von Varianten nicht länger zielführend ist.
Daher hat das DK-FBREK eine Drittmittelförderung eingeworben. Ziel des für 3 Jahre durch die Deutsche Krebshilfe
Deutsche Krebshilfe
im Rahmen des Prioritätenprogramms „Translationale Onkologie“ geförderten HerediVar Projektes (Fördernummer: 70114178) ist es, eine Datenbankplattform zu entwickeln, welche
die kollaborative Klassifikation von genetischen Varianten unter Automatisierung vieler Annotations- und Arbeitsschritte ermöglicht und so zukünftig die Bearbeitung
einer großen Zahl von Varianten und die Einspeisung der konsentierten Variantenbewertung des Konsortiums in die frei zugängliche ClinVar-Datenbank ermöglicht.
Weitere Informationen zum HerediVar Projekt und den beteiligten Institutionen finden sie unter der Projektbeschreibung. Für Anfragen nutzen sie bitte das
Kontaktformular.
Overview
Currently, there are 43963 variants in the HerediVar database of which 289 are classified. These are annotated using these databases:Title |
Description |
Version |
Version date |
|---|---|---|---|
| rsid | The rs-number of a variant from dbSNP (version summary: https://www.ncbi.nlm.nih.gov/projects/SNP/snp_summary.cgi) | 155 | 2021-06-16 |
| phylop_100way | PhyloP 100 vertebrates (100-way) conservation scores. These scores measure evolutionary conservation at individual alignment sites. Interpretations of the scores are compared to the evolution that is expected under neutral drift. Positive scores: Measure conservation, which is slower evolution than expected, at sites that are predicted to be conserved. Negative scores: Measure acceleration, which is faster evolution than expected, at sites that are predicted to be fast-evolving. | - | 2013-12-01 |
| cadd_scaled | The scaled CADD scores: PHRED-like (-10*log10(rank/total)) scaled C-score ranking a variant relative to all possible substitutions of the human genome (8.6x10^9). These scores range from 1 to 99. A cutoff for deleteriousness can be set to 10-15, but the choice remains arbitrary. | v1.6 | 2020-04-11 |
| revel | The REVEL pathogenicity score of this variant. This score can range from 0 to 1, which reflects the number of trees in the random forest that classified the variant as pathogenic. Thus, higher values represent a more "certain" decision. When choosing a cutoff one should keep in mind that higher cutoffs will result in a higher specificity, but lower sensitivity. | v1.3 | 2021-05-03 |
| spliceai_details | Details about the SpliceAI predictions: These include delta scores (DS) and delta positions (DP) for acceptor gain (AG), acceptor loss (AL), donor gain (DG), and donor loss (DL). Format: GENE|DS_AG|DS_AL|DS_DG|DS_DL|DP_AG|DP_AL|DP_DG|DP_DL | v1.3.1 | 2021-09-07 |
| spliceai_max_delta | Max of delta scores for acceptor gain, acceptor loss, donor gain and donor loss. A value of 0.5 or more can be assumed to have an impact on splicing. | v1.3.1 | 2021-09-07 |
| gnomad_ac | gnomAD alternate allele count for samples | v3.1.2 | 2021-10-22 |
| gnomad_af | gnomAD frequency of alternate allele in samples | v3.1.2 | 2021-10-22 |
| gnomad_hom | gnomAD number of homozygous individuals in samples | v3.1.2 | 2021-10-22 |
| gnomad_hemi | gnomAD number of hemizygous individuals in samples | v3.1.2 | 2021-10-22 |
| gnomad_het | gnomAD number of heterozygous individuals in samples | v3.1.2 | 2021-10-22 |
| gnomad_popmax | gnomAD population with maximum allele frequency (AF) | v3.1.2 | 2021-10-22 |
| gnomadm_ac_hom | Allele count restricted to variants with a heteroplasmy level >= 0.95 from the GnomAD mitochondrial genome data. These variants are (almost) homozygous among all mitochondria in an individual | v3.1 | 2020-11-17 |
| brca_exchange_clinical_significance | Variant pathogenicity as displayed in the Summary view of the BRCA exchange database | 54 | 2022-02-22 |
| flossies_num_afr | Number of individuals with this variant in the african american cohort. (n=2559) | - | 2022-03-25 |
| flossies_num_eur | Number of individuals with this variant in the european american cohort. (n=7325) | - | 2022-03-25 |
| cancerhotspots_ac | Number of samples showing the variant from cancerhotspots | v2 | 2017-12-15 |
| cancerhotspots_af | Allele Frequency of the variant (AC / num samples cancerhotspots) | v2 | 2017-12-15 |
| tp53db_class | Family classification: LFS = strict clinical definition of Li-Fraumeni syndrome, LFL = Li-Fraumeni like for the extended clinical definition of Li-Fraumeni, FH: family history of cancer which does not fulfil LFS or any of the LFL definitions, No FH: no family history of cancer, FH= Family history of cancer (not fulfilling the definition of LFS/LFL), No= no family history of cancer, ?= unknown | r20 | 2019-07-01 |
| tp53db_DNE_LOF_class | Functional classification for loss of growth-suppression and dominant-negative activities based on Z-scores | r20 | 2019-07-01 |
| tp53db_DNE_class | Dominant-negative effect on transactivation by wild-type p53. Yes: dominant-negative activity on WAF1 and RGC promoters, Moderate: dominant-negative activity on some but not all promoters, No: no dominant-negative activity on both WAF1 and RGC promoters, or none of the promoters in the large studies. | r20 | 2019-07-01 |
| tp53db_domain_function | Function of the domain in which the mutated residue is located. | r20 | 2019-07-01 |
| tp53db_transactivation_class | Functional classification based on the overall transcriptional activity | r20 | 2019-07-01 |
| task_force_protein_domain | The description of the protein domain from a hand-crafted table by the VUS-Task-Force. | - | 2022-06-01 |
| task_force_protein_domain_source | The source of the task force protein domain. | - | 2022-06-01 |
| hexplorer | The HEXplorer delta score (HZEI mutant - HZEI wildtype). HZEI scores were normalized by the total number of nucleotide positions which contribute to the score. | 1.0 | 2022-06-30 |
| hexplorer_mut | The HEXplorer score for the mutant sequence. HZEI scores were normalized by the total number of nucleotide positions which contribute to the score. | 1.0 | 2022-06-30 |
| hexplorer_wt | The HEXplorer score for the reference sequence. HZEI scores were normalized by the total number of nucleotide positions which contribute to the score. | 1.0 | 2022-06-30 |
| hexplorer_rev | The HEXplorer delta score for the reverse complement of the original sequence (HZEI mutant rev - HZEI wildtype rev). HZEI scores were normalized by the total number of nucleotide positions which contribute to the score. | 1.0 | 2022-06-30 |
| hexplorer_rev_mut | The HEXplorer score for the reverse complement of the mutant sequence. HZEI scores were normalized by the total number of nucleotide positions which contribute to the score. | 1.0 | 2022-06-30 |
| hexplorer_rev_wt | The HEXplorer score for the reverse complement of the reference sequence. HZEI scores were normalized by the total number of nucleotide positions which contribute to the score. | 1.0 | 2022-06-30 |
| max_hbond | The HBond delta score (max HBond mutant - max HBond wildtype). This score shows the change in binding affinity of the U1 snRNA to the splice site motiv, i. e. its ability to form hbonds with the sequence motiv. Negative values show that the mutant sequence is less probable to bind the U1 snRNA (This is a "worse" binding site). Positive values mean that the mutant sequence is more likely to bind the U1 snRNA. If there are multiple possible splice sites only the max values are considered. | 1.0 | 2022-06-30 |
| max_hbond_mut | The max HBond score for the mutant sequence. | 1.0 | 2022-06-30 |
| max_hbond_wt | This is the max HBond score for the reference sequence. | 1.0 | 2022-06-30 |
| max_hbond_rev | The max HBond delta score for the reverse complement of the original sequence (HZEI mutant rev - HZEI wildtype rev). This score shows the change in binding affinity of the U1 snRNA to the splice site motiv, i. e. its ability to form hbonds with the sequence motiv. Negative values show that the mutant sequence is less probable to bind the U1 snRNA (This is a "worse" binding site). Positive values mean that the mutant sequence is more likely to bind the U1 snRNA. If there are multiple possible splice sites only the max values are considered. | 1.0 | 2022-06-30 |
| max_hbond_rev_mut | This is the max HBond score for the reverse complement of the mutant sequence. | 1.0 | 2022-06-30 |
| max_hbond_rev_wt | This is the max HBond score for the reverse complement of the reference sequence. | 1.0 | 2022-06-30 |
| gnomad_popmax_AF | The allele frequency of the "popmax" population | v3.1.2 | 2021-10-22 |
| maxentscan | The transcript specific MaxEntScan scores calculated from ngs-bits. Each value is of the form: ref|alt | v1.0.0 | 2023-09-27 |
| maxentscan_swa | The transcript specific MaxEntScan SWA scores calculated from ngs-bits. A special application of the MaxEntScan algorithm to discover de-novo spliceing variants. Each value is of the form maxentscan_ref_donor|maxentscan_alt_donor|maxentscan_donor_comp|maxentscan_ref_acceptor|maxentscan_alt_acceptor|maxentscan_acceptor_comp | v1.0.0 | 2023-09-27 |
| gnomad_popmax_AC | The allele count from the popmax population from GnomAD | v3.1.2 | 2021-10-22 |
| bayesdel | Missense variant functional predictions by BayesDel tool (Feng 2017) used without allele frequency. Score bigger or equal to 0.16: damaging; Score smaller than 0.16: tolerated. Scores were imported from dbNSFP. | 4.4 | 2023-05-06 |
| cosmic | The COSV ID from COSMIC | - | 2023-06-06 |
| coldspot | Whether the variant is in a coldspot region or not | - | 2024-01-12 |
| cancerhotspots | The oncotree symbol, cancertype, tissue and number of occurances form the cancerhotspots database | v2 | 2017-12-15 |
| gnomad_ac_nc | The gnomAD allele count of the non-cancer subset | v3.1.2 | 2021-10-22 |
| gnomad_af_nc | The gnomAD allele frequency of the non-cancer subset | v3.1.2 | 2021-10-22 |
| gnomad_hom_nc | The number of homozygotes in the gnomAD non-cancer subset | v3.1.2 | 2021-10-22 |
| gnomad_hemi_nc | The number of hemizygotes in the gnomAD non-cancer subset | v3.1.2 | 2021-10-22 |
| gnomad_het_nc | The number of heterozygotes in the gnomAD non-cancer subset | v3.1.2 | 2021-10-22 |
| faf95_popmax | Filtering allele frequency (using Poisson 95% CI) for the population with the maximum allele frequency | v3.1.2 | 2021-10-22 |
| pfam_domains | The Pfam protein domain accession ids of all transcripts. Multiple values are separated with , - symbols. This data is generated by VEP. | 110 | 2023-07-18 |
| clinvar | The Variation ID from ClinVar | - | 2024-07-16 |
| hci_prior | The prior probability of pathogenicity as reported in the priors HCI website. These range from 0.97 for variants with high probability to damage a donor or acceptor to 0.02 for exonic variants that do not impact a splice junction and are unlikely to create a de novo donor. | 1 | 2024-08-23 |
| heredicare_vid | The VID from HerediCare.The version_date is inaccurate. They are always up to date when reimporting from heredicare. | - | 2024-08-23 |
| heredicare | The HerediCaRe annotation. Including LR scores and n_pat and n_fam | - | 2024-08-23 |
Changelog
v 1.14.4 (03.11.2024)
General changes:
- Added shortcut to insert unknown variants from variant display page
v 1.14.3 (15.10.2024)
General changes:
- Consensus classified variants can now be downloaded publically
v 1.14.2 (15.10.2024)
General changes:
- Added class "R" to SVI adaptation scheme
- Improved security for API
- Fixed bug where mails were not sent to new created users
- All final classifications are now shown properly in no_scheme classification scheme
v 1.14.1 (30.08.2024)
General changes:
- Improved stability of HerediCaRe uploads
- HerediCaRe and ClinVar upload stati are now loaded in the background on variant display pages
- Improved and fixed some issues with HerediCaRe and ClinVar upload status display and update
v 1.14 (23.08.2024)
General changes:
previous changelog
- Added ACMG schemes for MMR genes (pms2, mlh1, msh2, msh6)
- Improved VCF downloads. Variant list VCFs must now be generated seperately prior to downloading. This allows for larger file downloads.
- Added upload state search
- Fixed some minor issues with HerediCaRe up- and downloads
- Downgraded CrossMap to v0.7.0 because v0.7.3 yields wrong results for specific variants
- Fixed a bug where the tooltip of status pills would persist if the pill was updated
- Fixed a bug where the user was able to search for deprecated variant ids using the browse variant table