Standardization of Somatic Variant Classifications in Solid and Haematological Tumours by a Two-Level Approach of Biological and Clinical Classes: An Initiative of the Belgian ComPerMed Expert Panel
Abstract
:1. Introduction
2. Results
2.1. Expert Panel
2.2. Variant Calling and Annotation
2.3. Biological Variant Classification Workflow
2.4. Exceptions to the Workflow
- The Ts gene TP53 is an exceptional gene because of the plethora of variants detected in many tumour types affecting almost every position of the p53 protein. Therefore, we advise to use two dedicated TP53 databases to assess variant pathogenicity. The International Agency for Research in Cancer (IARC) TP53 database (http://p53.iarc.fr/) compiles various types of information on human TP53 variations in relation to cancer [26]. The second database, Seshat (http://vps338341.ovh.net/), can be used for (predicted) functional consequences of protein changes. The tumour-related outcome is presented in the downloadable Summary report. The consensus class indicated by both tools will be used for TP53 variant classification. However, in comparison with the ERIC recommendations [27] that classify the −2, −1 and +1, +2 exon flanking splice variants as Pathogenic, we mark them as Likely Pathogenic since these variants are actually not different from frameshift variants that are also classified as Likely Pathogenic by ERIC. Secondly, synonymous changes that are predicted to affect splicing are classified as Pathogenic by ERIC. Importantly, synonymous changes in P53 should also be checked for a detrimental functional effect in both TP53 databases.
- The BRCA1 and BRCA2 Ts genes are specifically analysed for variants in gynaecological tumours of the ovary and endometrium, as well as in cancers from breast, pancreas and prostate. In these cases, clear LoF variants (nonsense, frameshift, splice sites) are always classified as Pathogenic, instead of Likely Pathogenic if classified via the ComPerMed workflow. Notably, LoF variants in the last exon as well as all other somatic variants need to be checked for their pathogenicity in different online databases including ARUP (http://www.arup.utah.edu/database/BRCA/), InterVar (http://wintervar.wglab.org/), ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/), Enigma (https://brcaexchange.org/) and LOVD (https://databases.lovd.nl/shared/genes).
- Sequencing stutters of short tandem repeats (STR), including homopolymers, often occur as sequencing errors that are present in Vcf files at low allele frequencies, typically lower than 5%. However, a true change at an STR site can be discriminated from a stutter if the VAF is significantly higher than the observed stutter error rate present in most samples. The VAF of each STR variant thus has to be checked and if higher than a validated lab-specific threshold, it should be regarded as a true event. This threshold has to be defined by each lab since it can be method or analysis-specific. Each true STR change has to follow the standard classification workflow. As the prime example, the frameshift c.1934dup in the Ts gene ASXL1 is often seen as a stutter error in many NGS workflows at VAFs up to 10% but can be also found as a true variant in AML samples with VAF’s above the lab-specific threshold, thus classifying it as Likely Pathogenic.
- Splice site variants should be restricted to the −2, −1 and +1, +2 exon flanking positions, which harbour the AG/GT consensus splice motif, except for the MET exon 14 and BRCA1 and BRCA2 splice regions that should be analysed more broadly. All splice site variants will be considered as loss-of-function variants (Likely Pathogenic class) even though it might result in an in-frame exon(s) deletion because loss of at least one exon will most likely functionally harm the protein as well.
- Splice site variants in exon 14 of MET have to be seen as a CPV and thus are biologically classified as Pathogenic.
- Out-of-frame indels in exon 9 of CALR, including the typical type I and type II mutations, as well as out-of-frame insertions in exon 11 of NPM1 should not be treated as frameshift variants but as Consensus Pathogenic Variants (CPVs). Therefore, they are classified as Pathogenic.
- Somatic in-frame indels in the bZIP domain of CEBPA should be regarded as Likely Pathogenic.
- Finally, population-specific very rare benign variants can be distinguished from true somatic variants by their presence in at least three region-specific samples, with VAFs close to 50%, irrespective of the tumour content or tumour type. Consultancy of neighbouring NGS labs is advised and follow-up of such Likely Benign variants is warranted.
2.5. The Clinical Report
3. Discussion
- (1)
- The minor allele frequency (MAF) threshold to assign a variant as a polymorphism (class Likely Benign or Benign) was set at 1% by ACMG and GESMD, which is especially important in the absence of paired normal tissue. We have lowered this threshold to 0.1% because of the much higher number of data since 2015, and the curation of population databases thereby minimising the contamination of somatic tumour variants. Moreover, this threshold is valid for ethnic-specific MAFs with at least 2000 alleles investigated [42], which can be consulted in gnomAD. Note however, that this MAF threshold can be influenced by the targeted NGS method employed [43]. Finally, variants in ASXL1, DNMT3A and TET2 with VAFs below 10% can be associated with Clonal Hematopoiesis of Indeterminate Potential (CHIP) [44] and thus should be interpreted with caution as their presence alone is no evidence for the presence of malignancy;
- (2)
- ACMG advises to use the genomic coordinates of variants to be able to query genomic databases and not to depend on transcripts that are prone to changes. We recommend to use the HGVS nomenclature with reference to the transcript ID with the NCBI accession number of the main transcript, with version (e.g., BRAF NM_004333.5). We anticipate to change to the Locus Reference Genomic (LRG) record (http://www.lrg-sequence.org/) as it contains a stable reference sequence. So far, not all genes acquired an LRG number, and since most annotation programs and databases do not yet include the LRG transcript numbers, we did not make this switch yet;
- (3)
- For splice variants, we only consider the intronic −2, −1 (AG) and +1, +2 (GT) consensus splice positions, except MET exon 14 and BRACA1/2. ACMG and GESMD also evaluates intronic and exonic variants in the proximity of the splice sites, which are subjected to in-silico splice prediction tools. However, because of the low specificity of these tools and the inherent requirement for functional confirmation, we are not in favour of this option;
- (4)
- We classify the LoF variants in the last exon in the same way as those in preceding exons. GESPD requires the further evaluation of these changes.
4. Conclusions
Supplementary Materials
Author Contributions
Acknowledgments
Conflicts of Interest
References
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Gene | Transcript ID | Hs1 | Hs2 | Hs3 | Hs4 | Hs5 | Hs6 | Hs7 | Hs8 | Hs9 | Hs10 | Hs11 | Hs12 |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
ALK | NM_004304.4 | F1174L | R1275Q | ||||||||||
BRAF | NM_004333.5 | G469A/E/R/V | D594G/M | T599-K601 if-del/ins | V600E/K/M/R | K601E | |||||||
BRCA1 | NM_007294.3 | all clear LoF variants (nonsense, frameshift, splice site) | |||||||||||
BRCA2 | NM_000059.3 | all clear LoF variants (nonsense, frameshift, splice site) | |||||||||||
EGFR | NM_005228.4 | G719A/C/S | ex19if-del/ins | ex20 if-ins | T790M | C797S | L858R | L861Q | |||||
ESR1 | NM_000125.3 | K303R | E380Q | V392I | S463P | V533M | V534E | P535H | L536H/P/Q/R | Y537C/N/S | D538G | ||
GNAS | NM_000516.5 | R201C/H | |||||||||||
H3F3A | NM_002107.4 | K28M | G35R/W | ||||||||||
HRAS | NM_005343.3 | G12C/D/S/V | G13C/D/R/S/V | Q61H/K/L/R | |||||||||
IDH1 | NM_005896.3 | R132C/G/H/L/S | |||||||||||
IDH2 | NM_002168.3 | R140L/Q/W | R172K/M/S | ||||||||||
KIT | NM_000222.2 | ex8 | ex9 | ex11 | ex11 | ex11 | ex11 | ex11 | ex13 | ex13 | ex14 | ex17 | ex17 |
D419 if-del | S501-F504 if-ins | K550-V560 if-indel | W557G/R | V559A/D | V560D | L576P | K642E | V654A | T670I | D816H/V/Y | N822K | ||
KRAS | NM_004985.4 | G12A/C/D/F/R/S/V | G13C/D/R/S/V | A59T | Q61H/K/L/R | K117N | A146T | ||||||
MET | NM_001127500.3 | ex14 skipping | |||||||||||
NRAS | NM_002524.4 | G12A/C/D/R/S/V | G13C/D/R/S/V | A59T | Q61H/K/L/R | K117N | A146T | ||||||
PDGFRA | NM_006206.5 | S566_E577 if-del | D842V | D842_I843 if-del | V561D |
Gene | Transcript ID | Hs1 | Hs2 | Hs3 | Hs4 | Hs5 | Hs6 |
---|---|---|---|---|---|---|---|
ASXL1 | NM_015338.5 | none | |||||
CALR | NM_004343.3 | ex9of-del | ex9of-ins | ||||
CEBPA | NM_004364.3 | none | |||||
CSF3R | NM_156039.3 | T618I | |||||
DNMT3A | NM_ 175629.2 | R882C/H | |||||
EZH2 | NM_004456.4 | Y646F/H/N/S | |||||
FLT3 | NM_004119.2 | ex14if-dup | D835A/E/H/V/Y | ||||
IDH1 | NM_005896.3 | R132C/G/H/L/S | |||||
IDH2 | NM_002168.3 | R140L/Q/W | R172K/M/S | ||||
JAK2 | NM_004972.3 | ex12 if-del/if-dup | V617F | ||||
KIT | NM_000222.2 | see CPV Solid list | |||||
MPL | NM_005373.2 | S505N | W515any ms | ||||
NPM1 | NM_002520.6 | ex11of-ins | |||||
RUNX1 | NM_001754.4 | none | |||||
SETBP1 | NM_015559.3 | D868N | G870S | ||||
SF3B1 | NM_012433.3 | E622D | R625C/H | H662Q | K666N/R/T | K700E | G742D |
SRSF2 | NM_003016.4 | P95H/L/R | P95_R102del | ||||
TET2 | NM_001127208.2 | none | |||||
TP53 | NM_000546.5 | R175H | Y220C | G245S | R248Q/W | R273C/H | R282W |
U2AF1 | NM_006758.2 | S34F/Y | Q157P/R | ||||
WT1 | NM_024426.5 | none |
Parameter | Score +2 | Score +1 | Score +0.5 | Score 0 | Score −1 |
---|---|---|---|---|---|
Total # of entries of that particular AA change at that position in COSMIC | Solid: ≥50 | 50 > x > 10 | / | ≤10 | / |
Hemato: ≥10 | 10 > x > 5 | / | ≤5 | / | |
In silico prediction tools SIFT and MutationTaster | / | / | Both damaging and deleterious | Other | / |
Harmful in functional studies (PubMed, JAX-CKB, MDA, MCG) | / | / | Yes | Not reported | No |
Described in at least one genomic db (CIVIC, ClinVar, OncoKb, VarSome) | / | / | As (Likely) Pathogenic | Not described/unknown | As (Likely) Benign |
Parameter | Example(s) |
---|---|
Sample ID (primary lab) | 123-45678 |
Sampling date | 16th January 2019 |
Date of sample received | 17th January 2019 |
Sample tumoral stage | primary, metastasis |
Sample anatomic site | colon, liver, blood, lymph node, … |
Sample type | resection, (trephine) biopsy, aspirate, … |
Sample procedure | FFPE, fresh frozen, fresh tissue, … |
Neoplastic cells (%) | 30%, na |
Sample quality | disclaimer if sample does not fulfill pre-analytical requirements |
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Froyen, G.; Le Mercier, M.; Lierman, E.; Vandepoele, K.; Nollet, F.; Boone, E.; Van der Meulen, J.; Jacobs, K.; Lambin, S.; Vander Borght, S.; et al. Standardization of Somatic Variant Classifications in Solid and Haematological Tumours by a Two-Level Approach of Biological and Clinical Classes: An Initiative of the Belgian ComPerMed Expert Panel. Cancers 2019, 11, 2030. https://doi.org/10.3390/cancers11122030
Froyen G, Le Mercier M, Lierman E, Vandepoele K, Nollet F, Boone E, Van der Meulen J, Jacobs K, Lambin S, Vander Borght S, et al. Standardization of Somatic Variant Classifications in Solid and Haematological Tumours by a Two-Level Approach of Biological and Clinical Classes: An Initiative of the Belgian ComPerMed Expert Panel. Cancers. 2019; 11(12):2030. https://doi.org/10.3390/cancers11122030
Chicago/Turabian StyleFroyen, Guy, Marie Le Mercier, Els Lierman, Karl Vandepoele, Friedel Nollet, Elke Boone, Joni Van der Meulen, Koen Jacobs, Suzan Lambin, Sara Vander Borght, and et al. 2019. "Standardization of Somatic Variant Classifications in Solid and Haematological Tumours by a Two-Level Approach of Biological and Clinical Classes: An Initiative of the Belgian ComPerMed Expert Panel" Cancers 11, no. 12: 2030. https://doi.org/10.3390/cancers11122030
APA StyleFroyen, G., Le Mercier, M., Lierman, E., Vandepoele, K., Nollet, F., Boone, E., Van der Meulen, J., Jacobs, K., Lambin, S., Vander Borght, S., Van Valckenborgh, E., Antoniou, A., & Hébrant, A. (2019). Standardization of Somatic Variant Classifications in Solid and Haematological Tumours by a Two-Level Approach of Biological and Clinical Classes: An Initiative of the Belgian ComPerMed Expert Panel. Cancers, 11(12), 2030. https://doi.org/10.3390/cancers11122030