Hereditary cancer testing: Challenges and opportunities for genomic centres

Hereditary cancer testing has become a valuable tool in healthcare, contributing to the understanding of individuals' susceptibility to cancer. Knowledge of the genetic factors underlying cancer vulnerability plays a crucial role in enhancing risk assessments, implementing targeted prevention strategies, and optimizing personalized treatment plans.

These advancements are crucial considering the alarming statistics from Cancer Research UK:

According to their latest report, someone in the UK is diagnosed with cancer every 2 minutes, and on average, 1 in 2 people will be diagnosed with cancer in their lifetime.

The global incidence of cancer has also seen a significant increase, with around 18 million new cases reported each year, and a further 2% increase is predicted in the next 2 years.1

Among all cancer types, breast, lung, prostate, and colorectal cancer account for over half of all new cancer cases diagnosed. Thus, challenges persist in providing healthcare professionals with comprehensive tools for effective hereditary cancer testing.

By examining genetic testing methodologies, identifying high-risk cancer genes, and interpreting test results, the goal remains to equip healthcare professionals with the necessary knowledge to effectively guide and counsel patients during the process of germline cancer testing. As well as, addressing challenges related to the implications of test results, promoting collaborative approaches, and adapting to the evolving field of genetic counselling, all of these are crucial in mitigating the impact of cancer on individuals' lives.

Hereditary cancers: a complex and challenging field

Detecting hereditary cancer still poses significant challenges for laboratories worldwide. Germline cancers are defined as those caused by inherited genetic variants within cancer susceptibility genes and account for 5-10% of all cancer cases,2 including breast, ovary, uterus, prostate, and cancers of the gastrointestinal system.

While molecular genetic testing can be used to determine if individuals carry specific inherited genetic variants, interpreting and effectively communicating test results present further complexities.

One of the primary hurdles is the complexity and diversity of cancer-related genes and mutations. Identifying specific genetic alterations requires advanced technologies and expertise, as well as access to comprehensive genetic databases for accurate interpretation.

Additionally, the high cost of genetic testing and the limited availability of specialized laboratories pose financial and logistical challenges.

For example, gene alternations within BRCA1 and BRCA2 are known to increase susceptibility to breast, ovarian and prostate cancer, and this affects 1 in 300-400 people.3 However, BRCA1 contains many repetitive sequences and has high GC content, making it prone to sequencing errors and alignment artifacts, increasing the likelihood of false-positive or -negative results, compromising the accuracy of testing.

The BRCA genes are not the only cancer risk genes; there are now over 100 genes recognised to enhance the risk of developing cancer and each gene can present hundreds of variants, making interpretation a challenge for any testing provider.

Additionally, each year Genomic directories, such as the National Genomic Test Directory UK are updated to include new targets. Recent updates to the NGT directory have seen the addition of 5 new genes: REST, DLST, SLC25A11, RNF43 and MDH2, which have an association to inherited cancer syndromes. The everchanging legislations, makes it difficult for genomic testing service laboratories to stay up to date as commercial kit providers are struggling to include all the clinically relevant targeted content in their products.

Unlocking genetic insights: NGS panels for hereditary testing

Genetic testing for hereditable cancers facilitates cancer risk assessments for individuals and can guide implementation of early and additional screening and surveillance programmes if necessary.

For a hereditary cancer test, DNA originating from a sample of blood or saliva is usually analyzed for the presence of inherited variants using next generation sequencing (NGS) and bioinformatic pipelines.

Even though saliva-based NGS has emerged as a promising tool for genetic analysis, it comes with its own set of challenges.

They often have low DNA concentrations and of poor quality, compared to other sources. They are therefore not accepted by some test providers, putting additional stress on patients that might be conscious of blood draws.

Moreover, while NGS panels can provide comprehensive gene coverage, it is important to note that not all genes are detected by commercially available solutions due to their complex nature or unique structural variations. Therefore, additional testing methods may be required to ensure a thorough evaluation of the genetic landscape.

Even if the field of genetics is constantly evolving, with new genes and variants being discovered regularly, outdated panels content keeps on hindering the accurate and up-to-date analysis, leading to prolonged turnaround times and potential diagnostic delays.

Multi-gene panel testing

There are two targeted NGS approaches that can be used for hereditary cancer testing:

  • panels specific for a cancer syndrome, or
  • a multi-cancer gene panel

Using a targeted panel for a specific cancer syndrome, such as breast cancer can be a cost-effective method to screen for genomic variants; however, the tissue of origin does not always reflect the genetics of the cancer.

Furthermore, a negative result from a single syndrome panel may lead to the requirement of further testing, which could mean re-sampling the patient as well as additional sequencing costs. A more favourable option would be to use a multi-gene panel that includes all genes associated with inherited cancer syndromes.

Using a multi-cancer gene panel to screen for germline mutations enables profiling of known genetic associations for inherited cancers, regardless of cancer type. This method can provide a cost-effective, streamlined solution for cancer risk assessment and maximizes diagnostic yield for individuals who have a personal or family history of mixed cancers, or those with an unknown family history.

A multi-gene panel eliminates the requirement to run multiple assays for different cancer or variant types and has proven to be a clinically viable option. However, the selection of a targeted NGS panel needs careful consideration as many panels cannot detect key hereditary cancer copy number variants (CNVs).

CNVs are a common source of genetic variation and are involved in many genetic disorders such as single exon BRCA1 and BRCA2 alterations and those involved in Lynch syndrome. CNV detection is quickly becoming a critical component of hereditary cancer diagnosis, with the UK NGT directory now stating that all genes must be tested for CNVs alongside single nucleotide polymorphisms (SNPs) and insertion-deletion (INDEL) analysis.

In addition, the UK Government and Genomic England have also stated that all CNV analysis should now be conducted by NGS rather than the previous 'gold standard' method of multiplex ligation-dependent probe amplification (MLPA). There is therefore a need to streamline laboratory processes and enable detection of all variants of SNVs, INDELs and CNVs using a single workflow and analysis pipeline.

GALEAS Hereditary Plus

The GALEAS HereditaryPlus panel is an example of a multi-gene NGS panel that can be used for hereditary cancer testing. This hybridization and capture panel has been carefully curated to target variants in 147 genes associated with an increased risk of hereditary cancer, giving 100% coverage of the UK GNT directory and enhanced content for improved CNV calling.

It is vital that the NGS approach chosen for hereditary cancer testing accurately and robustly detects variants with high recall and precision.

The GALEAS HereditaryPlus panel has been specifically optimized for confident germline variant calling and has 100% SNV recall across a wide range of alteration types including small and large (>10bp) INDEL variants. It also contains 24 SNPs for identity tracking.

In addition, the GALEAS HereditaryPlus has enhanced content and CNV support regions covering introns and break points which improves CNV calling of key cancer susceptibility loci. The incorporation of commercial bioinformatics pipelines provides optimised CNV analysis; as has shown to give clinical utility by detecting CNVs with 96.6% sensitivity and 99.6% specificity.

The hereditary testing panel can also distinguish mosaic CNVs and pseudogenes such as PMS2 associated with Lynch syndrome, as well as detecting standard CNVs, making it suitable for detecting both common and rarer forms of hereditary cancers such as Phaeochromocytoma and paediatric cancers like Wilms tumor.

What to do if you would like to get tested?

All cancer cells contain genetic variants which have either accumulated over time or been inherited from a parent. For individuals, who have a family history of cancer, or have been diagnosed with rarer cancer clinical features, it may be useful to find out if any inherited variants are contributing to an increased cancer risk.

For anyone considering or wanting to implement hereditary cancer testing, visit our website, or if you are looking for a testing service, please get in touch and we can put you in contact with a service provider.


    1. Cancer Statistics for the UK. Cancer Research UK. 2023. Accessed December 1, 2023
    2. Inherited Cancer Genes and Increased Cancer Risk. Cancer Research UK. 2023. Accessed December 1, 2023
    3. Petrucelli N, Daly MB, Pal T et al. BRCA1- and BRCA2-Associated Hereditary Breast and Ovarian Cancer. Gene Reviews. 2022;1-33.