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Table 3 Sample genomic report with several mutations of interest, which have varying degrees of actionability. Key information available through the CIViC [78, 149] and OncoKB [77, 150] databases for each variant is displayed in the table below the example report. The details of the CIViC variant evidence score [78, 149] and The OncoKB level of evidence system [77, 150] are available in the literature and on the relevant websites. Column 4 of the table displays the respective tier that the mutation falls into based on the AMP/ASCO classification for the interpretation of sequence variants in cancer [86]

From: Molecular profiling for precision cancer therapies

Mock molecular profiling report
Patient identification
 Name: Doe, Jane
 Subject number: XXXXXXXXX
Diagnosis
 Tumor site/histology: head and neck/salivary
Specimen(s) received
 1. Consult slides—unstained—19:S1234
 2. Consult slides—stained—19:S1234
Sample identifier: SEQ-01-1234
Results
 NGS panel results: positive
 Variant 1: MAP2K1 (NM_002755.3)
  c.171G>C (p.Lys57ASn)
  Percent variant: 42.5%
 Variant 2: TP53 (NM_000546.5)
  c. 469G>T (p.Val157Phe)
  Percent variant: 38.7%
 CNV 1:ERBB2 amplification
  Copy number: 177.0
 Fusion 1: not detected
Methodology
Genomic DNA and RNA was extracted and analyzed using an NGS Panel that examines the coding regions (± 10 bp) of 500 genes using target enrichment hybrid capture followed by paired-end sequencing on the next sequencing platform. Variant calls are generated using a custom bioinformatics pipeline with alignment to genome build GRCh37/hg19. Minimum acceptable coverage for all reported genomic regions is > 200. The reportable range is 10–100% variant allele frequency. Test sensitivity is > 98% for detection of substitutions, small insertions or deletions, copy number changes, and RNA fusions. Large insertions or deletions, gene amplifications or loss, and some fusions may not be detected by this assay. Variants are interpreted only as somatic tumor variants because testing of DNA from germline tissue was not performed. Current methods may not detect all of the variants present in the genes tested.
Interpretation
VariantCIViC database [78, 149]OncoKB database [77, 150]Standards and guidelines for the interpretation and reporting of sequence variants in cancer [86]
MAP 2 K1 (NM_002755.3)
c.171G>C (p.Lys57ASn)
MAP2K1 is a dual-specificity kinase involved in the ERK pathway. Activating mutations have been seen in ovarian, melanoma, and lung cancers. Inhibitors of MEK genes have been shown to inhibit tumor growth.
Evidence for K57N: 2 references
This variant does not have a specific summary page
Variant type: missense
CIViC variant evidence score: 9.5
Drugs: selumetinib
Oncogenic: yes
Mutation effect: gain-of-function
Citations: 4 references
Cancer type: low-grade serous ovarian cancer, melanoma, non-small cell lung cancer, histiocytosis
Drugs: cobimetinib, trametinib
Level of evidence: 3A
Tier IID—potential clinical significance
Preclinical trials: few case reports without consensus
• Rare in the head and neck (TCGA)
• Gain-of-function variant
TP53 (NM_000546.5)
c. 469G>T (p.Val157Phe)
TP53 mutations are universal across cancer types. Majority of mutations localize to the DNA binding domain
Evidence for DNA binding mutation: 2 references
Variant type: DNA binding site
CIViC variant evidence score: 35
Drugs: none
Oncogenic: likely
Mutation effect: likely loss-of-function
Citations: 3 references
Drugs: none
Level of evidence: N/A
Tier IID—potential clinical significance
Preclinical trials: few case reports without consensus
• Non-functional variant (IARC TP53 database)
• Seen in the head and neck (TCGA, COSMIC)
ERBB2 amplificationERBB2/HER-2 is amplified or overexpressed in 20–30% of invasive breast cancers, commonly treated with HER-2 targeted therapy.
Evidence for amplification: 60 references
Variant type: transcript amplification
CIViC variant evidence score: 822.5
Drugs: trastuzumab, pertuzumab, neratinib, lapatinib, TDM-1, afatinib, cetuximab
Oncogenic: yes
Mutation effect: gain-of-function
Citations: 6 references
Cancer types: breast cancer, esophagogastric cancer, uterine serous carcinoma
Drugs: lapatinib, trastuzumab, TDM-1, neratinib, pertuzumab
Level of evidence: 2B
Tier IIC—potential clinical significance.
FDA-approved therapy for different tumor site
• ERBB2 inhibitors used in metastatic breast cancer
• ERBB2 amplifications seen in head and neck (TCGA, COSMIC)
Not approved for head and neck tumors
High TMBNo specific reference pageNo specific reference pageNo suitable category