Introduction of home and data page


Introduction of home page

1. Filter your job that running on DISSECT

2. Filter a gene by input symbol, gene ID, synonyms and location et. al.

Introduction of data page

1. Select samples for analysis

2. Choose an available tool for the selected samples

Knowledge base help


Knowledgebase process diagram

Knowledge base evidence level

Evidence of database consists of four categories: A, B, C and D, each category is defined as below:

Level A

Annotation for a variant-drug combination in medical society-endorsed guideline, or implemented in major health system.

Inclusion criteria:

(1) The genes that NCCN recommends to test

(2) Target genes that FDA approved or FDA recommends to test in certain cancer

Content includes:

(1) Genes NCCN recommends detecting in common cancers

(2) Target genes that FDA approved in certain cancer

(3) Level 1A evidences in PKGB database (PKGB database has its own classification system , it is mainly used in our chemotherapy drugs interpretation)

Level B

Level B annotates for a variant-drug interaction where the cohorts are more than 100. The association of significance should be exists in one study at least. Level B is subdivided into B1 and B2.

B1 Inclusion criteria:

(1) Annotation for a variant-drug combination where the preponderance of evidence shows a significant. The association of significance must be replicated in more than 100 samples.

B2 Inclusion criteria:

(1) B2: Annotation for a variant-drug combination where the preponderance of evidence shows a single significant while there could be other studies without significant. The association should be proved in more than 100 samples.

Content includes:

(1) Variant-drug combination proceeds in the phase III trial where the drugs are studied beyond approval cancer type.

(2) Variant-drug combination proceeds in the phase III trial on the drugs that haven’t been approved by FDA.

(3) Radiation therapy study that the preponderance of evidence shows a single significant. The association should be proved in more than 100 cohorts.

(4) Drugs metabolism study (metabolic database).

(5) Clinical research assesses prognosis makers. The association should be significant in above 100 cohorts.

(6) Chemotherapy evidence exists in PKGB database with the level 1B, 2B.

Level C

Level C is subdivided into C1 and C2

C1 annotates for two conditions. One condition is that the variant-drug combination shows significant in at least a study that the cohorts are more than 20 and less than 100. The other condition is that the variant-drug combination should be replicated in more than 20 cohorts but the studies that do not show statistical significance.

C1 Inclusion criteria:

(1) Study proceeds in cohorts more than 20 and less than 100. The variant-drug combination could evaluate in multiple studies, the association should be significant in at least one study.

(2) Study proceeds in cohorts more than 20. The variant-drug combination should be replicated in multiple studies, the association may not show clear significant.

C1 annotates for several conditions. The cohorts may be less than 20.The variant-drug combination just exists in a study and association shows no clear significant. The study is case report or in vitro.

C2 Inclusion criteria:

(1) Annotation for a variant-drug combination in a single study where the cohorts are more than 20 but lacking clear evidence association.

(2) Annotation for a variant-drug combination in a single study where the cohorts are less than 20, the association is significant or not.

(3) The variant-drug combination could evaluate in multiple studies where the cohorts are less than 20. The studies that do not show statistical significance

(4) Case report.

(5) The study is in vitro, such as cell lines or animal model.

Content includes:

(1) The study of variant-drug combination proceeds beyond approved cancer, the trail has not reach phase III.

(2) The study of variant-drug combination proceeds on the drug that the FDA has yet to approve, and the trail has not reach phase III.

(3) Radiation therapy study that the effect is assessed in less than 100 cohorts.

(4) Clinical research assesses prognosis makers. The study proceeds in less than 100 cohorts.

(5) Chemotherapy evidence exists in PKGB database with the level 3(C1), level 4 or NA (C2).

Level D

Inclusion criteria:

Tumor related genes that have no variant-drug combination reported.

Content includes:

(1) Genes in cancer pathways that have no variant-drug combination reported, or only about the molecular or functional assay evidence.

(2) Genes with high frequency variations in Cosmic.

Variation category

I: The US. FDA or the CFDA approved for the medical treatment of the cancer (including specific instructions mentioned variation, as well as all drug targets for gene mutations);There was a clear diagnosis/treatment/prognostic variation in the diagnostic guidelines (NCCN).

II: The mutations have not yet list in the guidelines, but have been written to the consensus of experts.

III: The US. FDA or the CFDA approved for other tumors can predict therapeutic gene variants;Or to describe a clear diagnosis/treatment/prognostic variation in other cancer types of authoritative diagnostic guidelines (NCCN).

IV: Non ongoing clinical trials or preclinical research.

V: Mainly clinical relevance is unknown or reported no relevant in the tumor research.

ACMG help


Introduction of Variants Classifier

The American College of Medical Genetics and Genomics (ACMG) published in 2015 the updated standards and guidelines for the clinical interpretation of sequence variants, based on 28 criteria. However, there are still extensive discrepancies among different laboratories.

Variant Classifier is a software tool based on ACMG guideline, aiming to standardize and automate clinical explanation of genetic variants. The input to Variant Classifier is set to be one of four formats: 1 coordinate on reference genome(Chromosome:Start-End:Ref:Alt), e.g. 13:32890598-32890598:A:G; 2 dbSNP ID, e.g. rs397507820; 3 cDNA change, e.g. BRCA1 c.T2413C; 4 amino acid change, e.g. BRCA1 E797K, and the output is the ACMG classification and detailed evidence explanation.

Instructions

1 Upload your variant with one of the following four formats:

1.1 coordinate on reference genome(Chromosome:Start-End:Ref:Alt),

e.g. 13:32890598-32890598:A:G;

1.2 dbSNP ID,

e.g. rs397507820;

1.3 cDNA change,

e.g. BRCA1 c.T2413C;

1.4 amino acid change,

e.g. BRCA1 E797K,

2 Click the ‘Search’ button

32890598-32890598 waiting for seconds, and the output will be shown with ACMG classification, evidence level, and detailed explanation

A blue question mark will be shown on the upper right of the ‘Evidence level’, and move your cursor there, a general instruction for varieties of evidence will be shown automatically.

When classification is ‘uncertain significance’, a gray question mark will exist, and move your cursor there, artificial tips will be shown automatically which can help clinical expert to search on other databases for supporting evidence to make a final judgment.

ACMG evidence level

  • Pvs1: wholegene deletion, stopgain, frameshift, or splicing mutation in 2bp
  • Ps1: same amino acid change as known pathogenic variants, with different nucleic acid alteration
  • Pm2: no record OR lower than 0.0003 in 1000g2015aug(ALL,EAS), exac03(ALL,_EAS)
  • Pm4: in-frame deletion/insertion OR stop codon loss which resulted the length change of translated protein
  • Pm5: same site as the known pathogenic variant with different nucleic acid change
  • Pp3: multiple lines of computational evidence support a deleterious effect on the gene or gene product
  • Pp5: reputable source recently reports variant as pathogenic
  • Pp6: ocated in the hotspot area or specific function domain
  • Ba1: Allele frequency is >1%
  • Bs1: Allele frequency is greater than expected for disorder
  • Bp1: missense variant while most pathogenic variants are truncating variants
  • Bp3: in-frame deletions/insertions in a repetitive region without a known function
  • Bp4: multiple lines of computational evidence suggest no impact on gene or gene product
  • Bp6: reputable source recently reports variant as benign
  • Bp7: a synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence