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and planning the initial management of cancer and rare inherited disorders, which often have a mendelian
inheritance pattern. There is a wider role of genomic medicine in population risk assessment, prognostic as-
sessment, companion tests [e.g., Estrogen receptor (ER) status in breast cancer] or comprehensive treatment
decision aids (e.g., oncotype diagnosis for breast cancer) and therapy monitoring (e.g., in acute leukaemias)
which are not discussed in detail.

The UK Clinical Genetics services
The following case history illustrates the sequence of events for a typical referral in the “pre-genomics” era.
We will go on to describe how the 100,000 Genomes Project is being used as a catalyst within the NHS to
introduce genomic medicine with linked diagnostics and therapeutics.

A 34-year-old lady presents to her primary care physician (general practitioner) in the UK NHS with a
breast lump. She is referred to her district general hospital breast (secondary) care team for an examination,
scan and a biopsy. A cancer diagnosis is made, and a date for surgery is set. A family history is taken, when
it is established that her paternal aunt was diagnosed with breast cancer under the age of forty. The patient
is referred to a specialist clinical genetics (tertiary care) service. She sees a counsellor to discuss the pros and
cons of having a BRCA1 and BRCA2 gene test. Germline genetic testing of a blood sample is undertaken in
the regional molecular laboratory. This demonstrates a pathogenic alteration in BRCA1 which is reported a
month post initial surgery. The clinical genetics department informs the patient, surgeon and the oncologist
to help plan if further preventative surgery is recommended. A cascade letter is written for relatives to access
predictive testing, screening and, when appropriate, reproductive counselling and/or risk-reducing surgery.
The patient is informed of relevant patient support groups and offered additional psychological support if
required.

In the near future, UK pathways for cancer diagnosis, or the investigation of rare Mendelian disorders will
change radically [Figure 1]. Much diagnostic genetic testing will move from clinical genetics departments.
Instead, it will be initiated by clinicians in the relevant specialty; this is called “mainstreaming”. Whole

genome sequencing (WGS) and whole exome sequencing will be done in consolidated laboratories. In an
attempt to improve our understanding and interpretation of genomic variation, phenotypic data will be col-
lected about patients to assist in the assessment of their genomic results. These approaches are a direct legacy
of the 100,000 Genomes Project.

The 100,000 Genomes Project
In 2012, the then Prime Minister David Cameron announced funding for the 100,000 Genomes Project, to
be organised by Genomics England (GE), a private company formed by the Department of Health in 2013.
Through this project, GE works in partnership with NHS England (itself a non-departmental public body of
the Department of Health) to integrate WGS into the NHS. The 100,000 Genomes Project aims to sequence
100,000 genomes from NHS patients with cancer and rare diseases. Data collected from the 100,000 Ge-
nomes Project can inform research on rare diseases, or benefit patient care potentially by streamlining the
diagnostic process and tailoring care to the individual.

The project has strict inclusion criteria, to ensure data of clinical and research benefit is gathered. For over
[1]
300 rare diseases, specific criteria are applied to maximise chance of recruiting individuals whose disease
[2]
may have a Mendelian basis. The project also requires submission of phenotypic data using SNOMED
(standardised healthcare terminology used for electronic health records and coding in over fifty countries
https://www.snomed.org/snomed-ct/what-is-snomed-ct) terms, and evidence of previous genetic testing (to
screen out previously known mutations). A patient’s whole blood samples must pass quality assurance and
quality control tests. When relevant, close relatives (usually the parents) of the patient also undergo WGS. In
the case of autosomal dominant conditions all affected members may be sequenced.