The East Genomics Cambridge Lab processes many of the haematological malignancy tests specified in the national genomic test directory via our Haem-Onc next generation sequencing (NGS) panel. This approach allows us to report on a wide range of genetic changes relevant to various clinical indications.
When the panel is used to process a test, we will report relevant genetic variants detected based on the requested test.
The Twist Haem-Onc NGS panel
The panel enables targeted NGS analysis and reporting of 108 genes (variants within full coding exons) relevant to haemato-oncology. It can detect single nucleotide substitutions and small insertion/deletion variants with a formal limit of detection of 5% variant allele frequency (VAF). This means genetic variants that are present in one gene copy within 10% of cells can be detected.
The panel is not adequately sensitive for minimal residual disease monitoring. Variants with a lower VAF are reported with a caveat that they are low level and should be interpreted with caution.
Details of all genes included in the panel, as well as the available targeted subpanels can be reviewed by downloading the file below. For each sample, the genes analysed will be detailed in the methodology section at the bottom of the report.
If information regarding variants in additional genes, that have been sequenced by the panel but not analysed or reported, is required this can be performed upon request by contacting the laboratory.
Interpreting reported variants
Variants are reported as “pathogenic”, “likely pathogenic” or a “variant of uncertain significance”. Reports will also indicate the prognostic significance of variants, where diagnosis is known (either from clinical details on the request form or from CUH HODS laboratory reports) and where prognostic associations are clearly established in the literature.
Annotations of whether variants are pathogenic are made by searching several databases of variants in cancer, together with databases of genomic variation from large population sequencing studies.
Pathogenic variants are typically those that have been reported recurrently in cancer but are absent or very rare in population studies, or alternatively have a very clear functional effect (e.g. a truncating mutation in a known tumour suppressor gene). There are no standardised criteria pathogenicity annotation in cancer so in-house consensus guidance is used.
Variants of uncertain significance are variants for which there is currently inadequate evidence to confidently support a pathogenic effect. These might represent rare germline variants that are of no consequence (single nucleotide polymorphisms), or acquired passenger mutations that have occurred in the cancer clone but do not contribute to the disease process. Others may be pathogenic, but there is not adequate information (e.g. reported recurrence in other cancers) to state this currently. Note that such information could change in future, but we will not review historical reports routinely unless requested to do so.
Some genes on the panel can be mutated in germline predispositions to haematological malignancies (e.g. RUNX1, CEBPA, DDX41). Where a potential germline variant is identified, reports may recommend further testing on a remission sample and/or germline sample. This should be performed after appropriate consent and some patients will require referral to clinical genetics.
Where variant annotation is particularly challenging or a possible germline variant is identified, cases may be referred to the haem-onc genomics tumour advisory board (GTAB) for further discussion, either before or after report verification.
The reporting team is always happy to discuss any variants if the interpretation is not clear from the report.