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]
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 | |||
Variant | 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 amplification | ERBB2/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 TMB | No specific reference page | No specific reference page | No suitable category |