Genetic Testing for Cancer

What is hereditary cancer?

Hereditary cancer is defined as cancer that has been caused by an inherited genetic variant. Inheriting certain genetic variants does not necessarily mean that cancer will develop but the lifetime risk is significantly increased. It is estimated that 5-10% of all cancer cases have a genetic variant that leads to cancer susceptibility. A genetic cause is suspected when the clinical features or family history include:

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early age of onset
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multiple primary tumours
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multifocal tumour sites
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bilateral tumour appearance in paired organs
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the same type of tumour in first or second-degree relatives or same tumour type clustering within a family
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rare tumour types
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rare tumours associated with birth defects
Not all genetic variants that lead to an increased susceptibility to cancer are associated with a family history. The Hereditary Cancer Panel offered by Informed Genomics Ltd (IGL) is available to anyone over 18 years of age who would like to know their cancer risk, regardless of personal or familial cancer history.

What are the benefits of hereditary cancer testing?

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Detect genetic variants associated with a predisposition to certain cancers
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Access to genetic counselling to explain test results, associated implications and support networks
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Identification of available risk management programmes and screening programmes
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Reduce the risk of developing associated cancers and aid early cancer detection
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Enable at risk family members to make informed choices   

How can Informed Genomics help?

IGL offers a range of hereditary cancer testing options to meet your requirements, from a complete clinical service to research applications. We can provide selected or multiple components of the testing pathway from sample collection, library enrichment, sequencing, bioinformatics, interpretation*, customised clinical reporting and genetic counselling.  

*Interpretation is only offered for approved genes. See Table 1 for details on genes that have been approved for clinical interpretation.

IGL Clinical Service

hereditary testing

The clinical service at IGL aims to identify individuals at a higher than population risk for hereditary cancer.

We offer a range of panels to study genes associated with the most common hereditary cancers ranging from a comprehensive multi-cancer panel to targeted panels for breast, ovarian, colorectal, prostate, melanoma and pancreatic cancer. The panels have been expertly curated using current literature and national testing guidelines to maximise clinical actionability, whilst minimising uncertainty. Our routine turnaround time for this testing is 3-4 weeks, however prioritisation options are available, please contact us to discuss your requirements. The final clinical report summarises test results by providing variant interpretation, the implications of the results and any recommended actions. Full genetic counselling is available. For further information on the clinical report see here.

The IGL 31 gene Comprehensive Hereditary Cancer Panel is the flagship panel for Informed Genomics Limited. The full gene list for this panel and the other panel options are shown in table 1.

Comprehensive Hereditary Cancer Panel APC, ATM1, BAP1, BARD1, BMPR1A, BRCA1, BRCA2, BRIP1, CDH1, CDK4, CDKN2A, CHEK22, EPCAM3, HOXB13, MLH1, MSH2, MSH6, MUTYH, NF1, NTHL1, PALB2, PMS24, POLD1, POLE, PTEN, RAD51C, RAD51D, SMAD4, STK11, TP53, VHL
Hereditary breast cancer panel ATM1, BARD1, BRCA1, BRCA2, CHEK22, PALB2, PTEN, STK11, TP53
Hereditary breast and gynaecological cancer panel ATM1, BARD1, BRCA1, BRCA2, BRIP1, CHEK22, EPCAM3, MLH1, MSH2, MSH6, PALB2, PTEN, RAD51C, RAD51D, STK11, TP53
Hereditary prostate cancer ATM1, BRCA1, BRCA2, CHEK22, EPCAM3, HOXB13, MLH1, MSH2, MSH6
Hereditary colorectal cancer (including Lynch syndrome) panel APC, BMPR1A, EPCAM3, MLH1, MSH2, MSH6, MUTYH, NTHL1, PMS24, POLD1, POLE, PTEN, SMAD4, STK11, TP53
Hereditary melanoma cancer panel BAP1, BRCA2, CDK4, CDKN2A, PTEN
Hereditary pancreatic cancer panel APC, BRCA1, BRCA2, CDKN2A EPCAM3, MLH1, MSH2, MSH6, PALB2, STK11, TP53, VHL

Table 1. The genes included in each panel.

Target region for all genes includes full coverage of exons and exon/intron boundaries up to +/- 20bp

Panel does not cover promoter, 5’ or 3’ UTR

Interpretation is based on the MANE transcript

1Reporting is restricted to the truncating or frameshift variants only and c.7271T>G variants in ATM.

2Truncating or frameshift variants in CHEK2.

3Exon deletion of exon 8 to 9 of EPCAM.

4PMS2 and its pseudogene PMS2CL share high sequence homology for exons 12-15. This test does not distinguish whether variants seen in PMS2 originate from PMS2 or PMS2CL. Further testing may be required to disambiguate any variants found in exon 12-15 of PMS2.

Further information regarding these genes can be found here

Research service

A larger research panel incorporating 129 genes is available for research only use. Raw data and secondary analysis services are available. 

Sample Submission

Our panels use genomic DNA extracted from Saliva samples.

A complete sampling kit containing sample collection tube and full instructions for use is provided. The kit is designed for self-sampling and can be dispatched directly to the client, either by Informed Genomics or through your own existing distribution pathways.

The sample is returned directly to the laboratory using a supplied prepaid returns container.

The sampling tubes provide long term stabilisation of the sample at room temperature, ensuring any delays in transit do not impact on the quality of the DNA extracted from the sample.

For more details on the submission pathways available please contact us.

The Technology

Our hereditary cancer testing service is delivered through our Next Generation Sequencing (NGS) pipeline. We use hybridisation library enrichment and Illumina sequencing to generate high quality sequencing data. An inhouse bioinformatics pipeline has been developed to detect single nucleotide variants (SNVs), indels and copy number variants (CNVs).
 
To ensure high confidence in the results, key performance parameters have been determined through extensive validation.

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Sensitivity (ability of assay to detect true positive results) was assessed using 323 SNVs, 48 (1-28bp) deletions/insertions variants, and 20 CNVs. 100% sensitivity was observed across all variant types.
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Based on sample size the 95% CI for sensitivity for SNVs is >98%, indels >92% and CNVs >83%. This is a measure of the confidence in the assay sensitivity and is based on the number of variants tested, therefore it is influenced by the availability of control samples, which for indels and CNVs is limited.
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Specificity (ability of assay to detect true negative results) was assessed by comparing true negative nucleotides from the ‘Genome In A Bottle’ consensus sequence with data generated using our Hereditary cancer comprehensive panel. Specificity >99.99% was achieved.
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Overall positive predictive value was estimated at >97%  
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Reproducibility was assessed across 6 repeat samples encompassing 80 variants. Results showed 100% reproducibility.

Quality Assurance 

The laboratory offers an efficient and effective, quality driven, service which ensures the high performance of our hereditary cancer testing service. This is underpinned by a strong and robust Quality Management System accredited to UKAS ISO 15189:2012

The Results

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What do the results mean?

Detection of a pathogenic or likely pathogenic variant means that a variant has been found that increases the risk of developing certain cancer, but this does not mean that cancer will definitely occur. Genetic variants can occur naturally as we get older, and they are also influenced by environmental and lifestyle factors. Hereditary cancer susceptibility is linked to genes known as tumour suppressors, we have two copies of these genes, and a single functional copy of the gene is sufficient at preventing cancer from developing; however, by having a pre-existing variant in a tumour suppressor gene, the risk of both copies being inactivated through a random second fault is increased. In essence, the cancer has been given a head start and if we are found to have these inherited genetic mutations, then our chances of developing certain types of cancers is higher compared to a person who does not have these genetic variations.

If no clinically relevant variant is detected, this means that we have not found any evidence of a genetic variant that is linked to cancer susceptibility. This lowers the risk of a genetic predisposition to cancer but does not exclude it. Variants can exist in genes not covered by the panel, as well as in genomic regions that fall outside of the scope of testing, such as deep intronic variants or in promoter regions. Participation in national screening programmes remains important, as well as adopting a healthy lifestyle, as at least 90% of cancers are sporadic.

How do we Interpret genetic variants?
  • Interpretation based on ACMG (American College of Medical Genetics), ACGS (Association for Clinical Genomics Science) and CanVar-UK (Cancer Predisposition Gene Variant Database) specifications.
  • Using evidence-based criteria variants are described as pathogenic, likely pathogenic, variants of unknown significance, likely benign and benign.
  • We standardise our interpretation utilising the latest clinical decision support software providing our HCPC registered scientists with the latest evidence and database resources for determining the pathogenicity of variants
What are variants of unknown significance (VUS)?

Variants of unknown significance are variants where there is either insufficient evidence to support whether they are pathogenic or benign, or the evidence is conflicting. As these variants cannot be acted on, they are not reported. As our understanding is constantly evolving due to continued research in this field VUS can change classification. If over time there is sufficient new evidence to support reclassification of a VUS to pathogenic, a new report will be issued. 

The Report

The report issued will contain all the actionable results from the test.

If a genetic variant is found, the report will provide the impact, implications, and recommended actions. These will be fully explained via the genetic counselling process.

The final report will provide a full description of any pathogenic or likely pathogenic variants detected, along with the clinical significance and recommended actions. The full result will be discussed during your genetic counselling appointment. Our genetic counsellor will also discuss health implications for you and your family. If no clinically significant variant is found, the report will clearly state this.

The Report

Contact us to find out more about our Hereditary Cancer Testing Service

Birmingham Research Park, 97 Vincent Drive, Birmingham