Settings

The report is generated with cpsr version 0.5.2.6, ( pcgr version 0.8.4.10), using the following key settings:

  • Genome assembly: grch38
  • Report theme (Bootstrap): default
  • Control population gnomAD: Global non-cancer subset
  • Upper MAF threshold (gnomAD) for unclassified variants included in report: 0.05
  • Show GWAS hits in report: TRUE
    • Minimum p-value for association: 0
  • Cancer predisposition geneset (virtual gene panel):

Summary of findings

Germline SNVs/InDels

Variant statistics

Variant numbers in the selected cancer predisposition genes (n = 215)

  • Number of SNVs: 19010
  • Number of InDels: 4550
  • Number of protein-coding variants: 114



Class 5 - Pathogenic variants


  • A total of n = 1 variants are registered with a Pathogenic clinical significance in ClinVar.
  • A total of n = 0 non-ClinVar variants (i.e. not registered in ClinVar) are classified with a Pathogenic significance by CPSR (ACMG criteria - based on population frequency and variant effect).


ClinVar






Non-ClinVar



Class 4 - Likely Pathogenic variants


  • A total of n = 0 variants are recorded with a Likely Pathogenic clinical significance in ClinVar.
  • A total of n = 0 non-ClinVar variants (i.e. not registered in ClinVar) are classified with a Likely Pathogenic significance by CPSR (ACMG criteria - based on population frequency and variant effect).



ClinVar



Non-Clinvar



Class 3 - Variants of Uncertain Significance (VUS)


  • A total of n = 108 variants are recorded with a VUS clinical significance in ClinVar.
  • A total of n = 5 non-ClinVar variants (i.e. not registered in ClinVar) are classified with a VUS significance by CPSR (ACMG criteria - based on population frequency and variant effect).



ClinVar






Non-Clinvar






Class 2 - Likely Benign variants


  • A total of n = 161 variants are recorded with a Likely Benign clinical significance in ClinVar.
  • A total of n = 0 Other variants (i.e. not registered in ClinVar) are classified with a Likely Benign significance by CPSR (ACMG criteria - based on population frequency and variant effect).


ClinVar






Non-Clinvar



Class 1 - Benign variants


  • A total of n = 920 variants are recorded with a Benign clinical significance in ClinVar.
  • A total of n = 2 Other variants (i.e. not registered in ClinVar) are classified with a Benign significance by CPSR (ACMG criteria - based on population frequency and variant effect).



ClinVar






Non-Clinvar








Genomic biomarkers

  • Here, variants in the sample that overlap with reported clinical biomarkers from the database for clinical interpretations of variants in cancer, CIViC are considered. Note that several variants in the query can overlap the same existing biomarker, given that biomarkers are reported at different resolutions (variant/gene level). Total number of clinical evidence items that coincide with query variants:
    • Predisposing: 1 evidence items
    • Predictive: 16 evidence items
    • Prognostic: 6 evidence items
    • Diagnostic: 0 evidence items



Predisposing


The table below lists all variant-evidence item associations:




Predictive


The table below lists all variant-evidence item associations:




Prognostic


The table below lists all variant-evidence item associations:




Diagnostic


No variant-evidence item associations found.






Secondary findings (ACMG SF v2.0)




GWAS hits


A total of 25 other germline variant(s) are associated with cancer phenotypes through genome-wide association studies (p-value < 5e-08 ):





Documentation

Introduction

This report is intended for interpretation of inherited DNA variants implicated with cancer susceptibility and inherited cancer syndromes. Variants in Class 1-5 are limited to a selected set of known cancer predisposition genes, for which the report lists ONLY those variants that are

  1. Previously classified in ClinVar (five-level significance scheme: pathogenic/likely pathogenic/VUS/likely benign/benign), or
  2. Coding variants not recorded in ClinVar with germline population frequency below the user-defined threshold, i.e. 
    • Minor allele frequency (MAF) < 0.05) in the user-defined population set in the gnomAD database

Annotation resources

The analysis performed in the cancer genome report is based on the following underlying tools and knowledge resources:

  • Software
    • VEP - Variant Effect Predictor (v98.3)
    • LOFTEE - Loss-Of-Function Transcript Effect Estimator (VEP plugin) (v1.0.3)
    • vcfanno - Rapid annotation of VCF with other VCFs/BEDs/tabixed files (v0.3.2)
    • vcf-validator - Validation suite for Variant Call Format (VCF) files, implemented using C++11 (v0.6)
    • vt - A tool set for short variant discovery in genetic sequence data (v0.57721)

  • Databases/datasets
    • GENCODE - high quality reference gene annotation and experimental validation (release 31/19)
    • dbNSFP - Database of non-synonymous functional predictions (v4.0 (May 2019))
    • Pfam - Collection of protein families/domains (v32 (September 2018))
    • UniProtKB - Comprehensive resource of protein sequence and functional information (release 2019_10)
    • gnomAD - Germline variant frequencies exome-wide (r2.1 (October 2018))
    • dbSNP - Database of short genetic variants (152/152)
    • DoCM - Database of curated mutations (release 3.2)
    • CancerHotspots - A resource for statistically significant mutations in cancer (2017)
    • ClinVar - Database of genomic variants of clinical significance (release 20191105)
    • CancerMine - Literature-mined database of tumor suppressor genes/proto-oncogenes (v18 - 20191101)
    • DiseaseOntology - Standardized ontology for human disease (20191030)
    • GWAS_Catalog - The NHGRI-EBI Catalog of published genome-wide association studies (20191014)
    • CIViC - Clinical interpretations of variants in cancer (November 5th 2019)

Variant classification


All coding, non-ClinVar variants in the set of cancer predisposition genes have been classified according to a five-level pathogenicity scheme (coined CPSR_CLASSIFICATION in the tables above). The scheme has the same five levels as those employed by ClinVar, e.g. pathogenic/likely pathogenic/VUS/likely benign/benign. The classification performed by CPSR is rule-based, implementing most of the ACMG criteria outlined in SherLoc (Nykamp et al., Genetics in Medicine, 2017), and CharGer. Information on cancer predisposition genes (mode of inheritance, loss-of-funcion mechanism etc.) is largely harvested from Maxwell et al., Am J Hum Genet, 2016.

The ACMG criteria listed in the table below form the basis for the CPSR_CLASSIFICATION implemented in CPSR. Specifically, the score column indicates how much each evidence item contribute to either of the two pathogenicity poles (positive values indicate pathogenic support, negative values indicate benign support). Evidence score along each pole (‘B’ and ‘P’) are aggregated, and if there is conflicting or little evidence it will be classified as a VUS. The contribution of ACMG evidence items pr. variant can be seen in the CPSR_CLASSIFICATION_CODE and CPSR_CLASSIFICATION_DOC variables.



References

Amendola, Laura M, Gail P Jarvik, Michael C Leo, Heather M McLaughlin, Yassmine Akkari, Michelle D Amaral, Jonathan S Berg, et al. 2016. “Performance of ACMG-AMP Variant-Interpretation Guidelines Among Nine Laboratories in the Clinical Sequencing Exploratory Research Consortium.” Am. J. Hum. Genet. 98 (6): 1067–76.

Huang, Kuan-Lin, R Jay Mashl, Yige Wu, Deborah I Ritter, Jiayin Wang, Clara Oh, Marta Paczkowska, et al. 2018. “Pathogenic Germline Variants in 10,389 Adult Cancers.” Cell 173 (2): 355–370.e14.

Maxwell, Kara N, Steven N Hart, Joseph Vijai, Kasmintan A Schrader, Thomas P Slavin, Tinu Thomas, Bradley Wubbenhorst, et al. 2016. “Evaluation of ACMG-Guideline-Based Variant Classification of Cancer Susceptibility and Non-Cancer-Associated Genes in Families Affected by Breast Cancer.” Am. J. Hum. Genet. 98 (5): 801–17.

Richards, Sue, Nazneen Aziz, Sherri Bale, David Bick, Soma Das, Julie Gastier-Foster, Wayne W Grody, et al. 2015. “Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.” Genet. Med. 17 (5): 405–24.




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