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Introduction Cancer is a common condition. Up to one in two people will develop cancer in their lifetime. Cancer is a genomic disease. While the word ‘cancer’ represents a multitude of distinct diseases which can arise due to different risk factors and occur in almost every tissue/cell type in the human body, all cancers arise due to changes, known as variants, in the DNA sequence of a cancer cell. Predominantly these variants occur in genes which impact on the regulation of cell division, cell growth and cell death.A person with cancer has two distinct genomesThe genetic variants present in the fertilised egg at conception, present in every cell within that individual, known as the constitutional or germline genome.The genetic variants present in the cancer cell, in addition to the constitutional variation, which arise from the acquisition of mutations through the process of mutagenesis, cell replication and division. This includes variation driving oncogenesis (driver variants) and variation acquired through the mutagenic processes affecting the cell over its lifetime, but not directly causative of the cancer process (passenger variants).While the majority of cancers are sporadic and due to acquired driver variants, constitutional genetic variation remains an important contributor to cancer susceptibility. In this article, we review the identification and management of genetic susceptibility to cancer.Identification and management of genetic susceptibility to cancer Section 1: Overview of susceptibility to cancer Monogenic risk Monogenic risk involves variants, classified as likely pathogenic or pathogenic, in single genes that significantly increase the likelihood of developing certain types of cancer. These genes are often termed ‘cancer susceptibility genes’ (CSGs). The variants are constitutional in nature and follow Mendelian patterns of inheritance. 1Most CSGs function as tumour suppressor genes or oncogenes. Tumour suppressor genes regulate cell growth, DNA repair and apoptosis, acting as cellular ‘brakes’.2 In hereditary cancer, individuals inherit one defective allele, with cancer emerging after loss of the second allele—the Knudson ‘two-hit hypothesis’.3 While this forms the basis of the genetic model of tumourigenesis, it is usually insufficient on its own to drive malignant progression. Cancer development is a multistep process that requires the accumulation of additional genetic and epigenetic alterations affecting oncogenes, tumour suppressor genes and DNA repair pathways4 5In contrast, oncogenic variants typically exert gain-of-function effects and activate growth-promoting pathways.6 Cancer predisposition due to variants in tumour suppressor genes is much more common than variants in oncogenes.Several common cancers, including breast, ovarian, prostate, bowel and endometrial, are strongly linked to inherited variants in tumour suppressor genes. BRCA1 and BRCA2, identified in 1994 and 1995,7 8 remain among the best-characterised CSGs, conferring markedly elevated risks of breast and ovarian cancer.9PALB2 functions as part of the homologous recombination pathway, similar to BRCA1/2, and confers a high lifetime risk of developing breast cancer.10 Large case–control studies have established truncating variants in ATM, BARD1, CHEK2, RAD51C and RAD51D as moderate risk breast cancer genes.11 12 This corresponds to a 2–4-fold increased risk of developing cancer,13 compared with >6-fold with high risk genes.Lynch syndrome, resulting from pathogenic variants in MLH1, MSH2, MSH6, PMS2 and deletions of the 3′ end of EPCAM, predisposes primarily to colorectal, endometrial and ovarian cancers. An association is also recognised for gastric, urothelial tract, small bowel, pancreas, biliary tract and sebaceous neoplasms of the skin.14 Cancer risk varies by gene, for example, colorectal cancer risk is substantially higher and earlier in MLH1 carriers than PMS2 carriers.15 16 Consequently, the UK has developed gene-specific screening recommendations.17A key example of oncogene-mediated monogenic cancer risk is RET-associated Multiple Endocrine Neoplasia type 2 (MEN2). Germline activating RET variants cause increased risks of medullary thyroid carcinoma, phaeochromocytoma and parathyroid adenomas.18 MEN2A and MEN2B represent distinct clinical subtypes. MEN2B is characterised by mucosal neuromas, gastrointestinal ganglioneuromatosis, marfanoid habitus and earlier, more aggressive cancer development.19 20 Management of cancer risk in MEN2 is guided by risk stratification based on the specific RET variant, which informs timing of surveillance and prophylactic thyroidectomy.21Many other CSGs exist but to cover all is outside of the scope of this article.22Polygenic risk Twin studies have indicated that heritability of breast cancer could be as high as 27% 23; however, CSGs are identified in less than 5% of cases.12 This implies the presence of additional contributing factors with polygenic risk proposed as one such influence.Application of polygenic risk is an emerging field of study in cancer genetics. It is estimated that throughout the human genome, there are 10 million single-nucleotide polymorphisms (SNPs) present.24 Many SNPs are part of natural variation and in isolation have minimal impact.In families with more than one individual affected by cancer, it remains a relatively rare occurrence to identify a pathogenic variant in a highly penetrant CSG. It is hypothesised that a larger proportion of cancer risk may be attributed to the cumulative effect of these multiple low-risk SNPs.25 Polygenic risk scores (PRS) have been produced by combining sets of significantly associated SNPs.26A UK-based study by Huntley et al27 suggested that breast, colorectal and prostate cancer would be most amenable to PRS stratification based on testing performance and higher disease incidence.In breast cancer, studies have shown PRS can improve risk prediction. Evans et al28 combined PRS with breast density on mammography and other classical risk factors for 10 000 women recruited to the Predicting Risk of Cancer at Screening study. The group showed that this approach improved breast cancer risk stratification. Gao et al29 demonstrated that the application of PRS in women carrying pathogenic variants in CHEK2 and ATM had the potential to restratify to a lower-than-expected lifetime breast cancer risk in 30% and 50% of cases, respectively. This enables more personalised management and potentially reduces over screening.McHugh et al30 undertook a comprehensive study of PRS use in prostate cancer. PRS in a cohort of 6393 individuals led to the identification of prostate cancer requiring clinical intervention in 103 participants. 71% of these cases would likely have been missed using the standard UK diagnostic pathway.Challenges exist in the use of PRS for risk stratification. The majority of participants in GWAS studies are of white European descent.31 Aside from an incomplete knowledge for diverse population groups, SNPs may exert differing effects in differing populations32 and many studies fail to stratify for age.33Additional risk factors The WHO estimates that 30–50% of cancer could be prevented through lifestyle modification for example, diet, maintaining physical activity, avoiding alcohol and smoking. 34 Lifestyle factors can influence cancer risk even among individuals with a genetic predisposition.35Using UK Biobank data for 195 822 individuals, Byrne et al36 assessed the impact that lifestyle factors have on the risk of developing 13 different cancer types. Adherence to World Cancer Research Fund recommendations was associated with a reduction in cancer risk for eight cancer types (colorectal, postmenopausal breast, lung, kidney, uterine, pancreatic, bladder and oral/pharyngeal). This is concordant with other studies which have shown healthy lifestyles are associated with lower risks of bladder, breast, colon, endometrial, oesophageal, kidney, liver, lung, rectal and gastric cancer.37When considering breast cancer, increasing age, greater height, nulliparity and older age at first birth are all associated with higher risk. Increased BMI in postmenopausal women is also a significant risk factor.38 More specifically, adult weight gain is independently associated with an increased risk of postmenopausal breast cancer with risk progressively rising with greater weight gain.39It has been demonstrated that adopting a healthy lifestyle reduces breast cancer incidence, even among women with high genetic risk.40Section 2: Assessment and identification of genetic cancer risk Genetic testing in patients affected by cancer Traditionally, in the UK, genetic testing for individuals with a personal and family history of cancer focused on identifying those with at least a 10% prior probability of having a CSG. 41 This figure considers that CSGs are detected in a minority of cases and other competing factors such as available resources and complexities of variant interpretation. Assessments of this probability can be based on factors such as age of onset of cancer,42 type of cancer present, histological features43 and family history.44Detection of CSGs has obvious benefits in terms of surveillance, treatment planning and cascade testing. Additionally, the cost of sequencing has substantially decreased with next-generation sequencing technologies and knowledge of variants has also improved.45 This is contributing to a drive to expand genetic testing beyond the 10% threshold.This will undoubtedly require new models of service delivery. An example of one such model is the BRCA-DIRECT programme, which was an NHS-integrated, digital-first genetic testing pathway that delivered testing through online information, digital consent, postal test kits and an optional helpline. Patients did not need to meet NHS Test Directory eligibility criteria. They could undergo testing if they had invasive breast cancer (or high-grade ductal carcinoma in situ), were over 18 years old and had not previously received BRCA1, BRCA2 or PALB2 testing.46Assessment using family history The Manchester Score is a well-established clinical tool used to estimate the likelihood of identifying a pathogenic variant in BRCA1 or BRCA2 in individuals with a personal/family history of breast and ovarian cancer. First introduced by Evans et al in 2004,47 the scoring system assigns points based on clinical criteria, with a score of 15 or higher indicating a ≥10% probability of detecting a pathogenic variant in BRCA1 or BRCA2. Subsequent revisions in 2009 and 2017 incorporated tumour pathology data to enhance its predictive accuracy.48 49Identification of those who would benefit from testing for Lynch syndrome was previously based on a family history assessment known as Amsterdam Criteria.50 While Amsterdam criteria demonstrate high specificity (approximately 98%) but sensitivity was relatively low (22–42%), meaning that over half of Lynch syndrome families remained untested.51Another example of using family history to guide genetic testing eligibility is the application of the Chompret criteria in relation to TP53. Building on the original clinical diagnostic framework established by Li and Fraumeni in 1969,52 the Chompret criteria improved the sensitivity of TP53 variant detection as it considered the spectrum of the condition and broadened eligibility.53Assessment using histology Assessment and investigation of tumour subtypes is important not only for therapeutic implications but also for consideration of genetic testing.Lynch syndrome is caused by pathogenic variants in MLH1, MSH2, MSH6, PMS2 and deletions of the 3′ end of EPCAM; all of which have a role in the mismatch repair pathway. This manifests molecularly as microsatellite instability (MSI), which can be assessed in tumours by immunohistochemistry (IHC) or MSI testing.54 MSI and IHC testing on colorectal and endometrial tumours is now established in routine clinical practice in the UK as a prescreen to initiate genetic testing for Lynch syndrome.In general, both MSI testing and IHC are considered as equally effective methods as prescreening to direct Lynch syndrome testing in the context of colorectal cancer. The choice of which to use as the initial screening tool typically depends on available resources and local laboratory expertise.55 For endometrial cancer, however, IHC outperforms MSI in this role.56Various cancer predisposition syndromes can present with tumours, which are highly characteristic. Examples include sex cord tumours with annular tubules, adenoma malignum of the cervix and Sertoli cell tumours of the testes in Peutz-Jeghers syndrome,57 L’hermitte-Duclos tumours in PTEN hamartoma tumour syndrome58 and spinal or cerebellar hemangioblastomas in Von Hippel-Lindau syndrome.59Assessment of syndromic features Some CSGs can present with a syndromic component beyond the associated cancer risk. Identification of these non-cancer features can indicate the need to consider genetic testing.PTEN hamartoma tumour syndrome amalgamates various clinically heterogenous syndromes including Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome60 caused by variants in the gene PTEN. Additional syndromic features noted within this syndrome include neurodevelopmental delay, macrocephaly and dermatological features such as macular pigmentation of the glans penis, trichilemmomas, acral keratosis and oral papillomatosis.58Gorlin syndrome, also known as nevoid basal cell carcinoma syndrome, is a hereditary cancer predisposition disorder caused by variants in PTCH1 and SUFU. It is characterised by an increased risk of developing basal cell carcinomas, often at a young age. In addition to its oncologic features, the syndrome may present with a range of developmental and structural anomalies including jaw keratocysts, palmar and plantar pits, cleft palate and polydactyly. Radiological findings can include lamellar (sheet-like) calcification of the falx cerebri on skull X-ray, as well as vertebral and rib anomalies. Some individuals may also develop ovarian or cardiac fibromas, contributing to the syndromic complexity of the condition.61 62Patients with cancers known to be associated with rare syndromes should have a clinical examination to assess for potential features and ensure appropriate genetic testing has been undertaken.Assessment using integrated data models Cancer risk assessment has progressed beyond monogenic models using algorithms that integrate genetic, personal and clinical factors. In UK practice, CanRisk, the web interface for BOADICEA, is the preferred breast and ovarian cancer risk prediction tool. It incorporates multigene panel testing results together with breast density, tumour pathology, family history, hormonal and reproductive factors, lifestyle information and PRS. 63–65CanRisk also estimates the probability of pathogenic variants in BRCA1/2, PALB2, CHEK2, ATM, BARD1, RAD51C, RAD51D and BRIP1. Current guidelines within the UK suggest genetic testing can be considered when the combined probability of a clinically actionable BRCA variant is ≥10%.66The Tyrer-Cuzick model was largely based on data produced from International Breast Intervention Study (IBIS)67 but has been updated to use similar variables.68 Within UK genetics services, CanRisk is favoured over Tyrer-Cuzick as the latter is felt to overestimate cancer risk.69For PTEN-related disorders, UK services also use the Cleveland Clinic PTEN Risk Calculator, which incorporates cancer history, head circumference, dermatological features, gastrointestinal polyposis and neurodevelopmental findings.70National Genomic Test Directory In January 2019, the NHS launched a nationally commissioned Genomic Medicine Service and a new National Genomic Test Directory was produced to standardise eligibility and access to genetic testing. 71 This now forms the basis of decision-making regarding genetic testing and incorporates much of the above assessment methodologies to determine testing eligibility.Other countries will have their own eligibility and testing protocols.Tumour testing Genetic analysis of tumour material has expanded through both tumour sequencing and circulating tumour DNA (ctDNA) testing.Tumours exhibit extensive genomic variation and instability, therefore selecting which genes and variants to pursue for germline follow-up requires careful consideration. The ESMO Precision Medicine Working Group guidelines identified 40 genes with a high germline conversion rate, meaning that variants detected in tumour-derived DNA are frequently pathogenic and of germline origin. These genes are grouped into three tiers of clinical actionability: most actionable, highly actionable and standard. This reflects their penetrance and the effectiveness of available risk-reducing interventions.72Variant selection for germline follow-up also depends on variant allele frequency (VAF), the proportion of sequencing reads carrying a specific genetic variant relative to the total reads. Variants with a VAF <30% are generally unlikely to represent germline findings. Some genes, notably TP53, accumulate somatic mutations across many tumour types, so even high-VAF variants have a low germline conversion rate.72In the UK, proposed national guidance aims to standardise germline follow-up from tumour testing.73 A modified intermediate-conservative strategy recommends germline testing across all tumour types for variants in seven highly actionable CSGs: BRCA1, BRCA2, PALB2, MLH1, MSH2, MSH6 and specific high-risk RET variants. For the remaining 33 CSGs, follow-up is advised only when variants arise in tumour types known to be linked to those genes. TP53 follow-up is limited to patients under 30 or those with brain tumours. Variants selected should be (likely) pathogenic, have a VAF of at least 30–40% or represent recognised founder variants.ctDNA testing is an emerging modality, now routinely available for lung cancer and advanced breast cancer.74 Interpretation depends on tumour fraction; when low, results may largely reflect germline DNA. Other factors, including patient age and the possibility of clonal haematopoiesis, must also be considered.73Genetic testing in patients unaffected by cancer Genetic testing in individuals unaffected by cancer represents a shift from traditional clinical practice. This can take several forms: some patients may be considered for testing based on family history, while others may have CSGs identified through alternative routes such as incidental findings, population screening programmes, or by choosing to undergo testing via direct-to-consumer (DTC) services.In the UK, the National Test Directory has commissioned germline testing in unaffected individuals with a family history of cancer, particularly in cases where no living relative is available for testing and somatic testing has been considered. Testing should be offered when the individual has an estimated ≥10% likelihood of carrying a monogenic variant, and their deceased first-degree relative had a ≥20% likelihood. Final decisions should be made through discussion at a specialist multidisciplinary team meeting.66Incidental findings An incidental finding is a clinically significant result that is unrelated to the primary reason for referral and was not intentionally sought during testing. 75 These findings can vary in nature and may include pathogenic variants unrelated to the initial clinical indication, carrier status for autosomal recessive conditions or unexpected information regarding biological relationships.A recent study by Fernández-Castillejo et al76 reported that incidental findings in CSGs were identified in approximately 1% of cases undergoing multigene panel testing. However, with expanding eligibility for genetic testing, improved bioinformatic pipelines and broader gene panel coverage, this figure is expected to rise.The British Society for Genetic Medicine (BSGM) has published national guidance to support consistent reporting of incidental CSG findings. The framework outlines criteria based on clinical actionability, penetrance and variant classification and includes a curated list of CSGs to guide decision-making.77Population testing Testing in the UK is shifting towards wider unaffected population-based testing to assist with risk stratification and focusing on early detection and prevention. The 10 Year Health Plan, published in 2025, sets a specific target of creating ‘a new genomics population health service’ to enable early detection of individuals at high risk of common diseases. 78The Generation Study, launched in the UK in 2024, is also supported in the 10 Year Health Plan. The genomes of 100 000 newborns will be sequenced with the aims of identifying rare conditions earlier, enabling research and exploring the risks and benefits of storing genomic data over a person’s lifetime79A further example of population-based testing is the NHS England Jewish BRCA Testing Programme. The programme offered testing to individuals with one or more Jewish grandparents due to the increased likelihood of having an Ashkenazi Jewish founder pathogenic variant in BRCA1 or BRCA2.80Direct to consumer testing DTC genetic testing refers to genomic tests purchased outside routine NHS care, usually online or through commercial providers. 81 Most DTC tests use SNP-chip genotyping, which often detects common variants but is prone to false positives, particularly for rare variants.82 83These tests create challenges for clinicians, laboratories and patients. There are concerns about accuracy, the NHS capacity to review commercial results and the complexity of interpreting reports. Patients may also lack adequate pre-test and post-test counselling or follow-up support. The BSGM’s updated 2025 position statement highlights ongoing difficulties and calls for increased government regulation.81Section 3: Implications of a diagnosis of enhanced genetic cancer risk and management of genetic susceptibility to cancer for the patient and their relatives Enhanced surveillance, prevention and detection In 2019, the UK government set a goal to increase the proportion of cancers diagnosed at stages 1 and 2 from 50% to 75%. 84 A key component to achieving this target will be identification of those at increased risk of cancer through genetic testing and implementing appropriate surveillance, prevention and detection measures.Many CSGs have established comprehensive surveillance and prevention guidelines. The approaches to breast, ovarian and bowel cancer will now be considered.Breast cancer Management of individuals with an inherited predisposition to breast cancer centres on enhanced surveillance and/or risk-reducing surgery. In the UK, women with pathogenic variants in BRCA1, BRCA2, PALB2, PTEN, STK11 or CDH1 enter the very high-risk screening (VHRS) programme. Screening may commence from age 25 for BRCA1/2 and PALB2 carriers, and from age 30 for women with the specific ATM c.7271T >G variant, variants in PTEN, STK11, CDH1 or biallelic CHEK2 variants.85 VHRS includes annual breast MRI from age of commencement to age 50 (downgraded to annual mammography only) if mammographic density drops to BiRads A, with annual mammography from age 40 to 70 following which annual self-referral for screening is required.For individuals with TP53 variants, annual breast MRI screening is recommended between the ages of 20 and 70 years. Similarly, for those with biallelic ATM variants, annual MRI surveillance is advised from age 25 to 70 years. Mammography is generally avoided in both groups due to increased sensitivity to ionising radiation and the associated elevated risk of radiation-induced malignancy.85Surveillance for those with moderate-risk genes (ATM, CHEK2, RAD51C, RAD51D) is based on individualised risk assessment, with most patients falling into high or moderate-risk screening pathways.86Table 1 below provides a summary of the recommended breast cancer surveillance strategies based on the estimated level of risk.Table 1Summary of UK moderate and high risk breast cancer screening recommendationsScreening ageModalityVery high riskGene dependent (25-30)Age dependent annual MRI and/or mammographyHigh risk40–59Annual mammographyModerate risk40–49Annual mammographyFor women unaffected by cancer, risk-reducing mastectomy can be considered when the lifetime risk of developing breast cancer is at least 30%.87 This threshold is typically met by individuals with pathogenic variants in BRCA1/2, TP53, PALB2 or ATM c.7271T>G. For other moderate-risk genes, individualised risk assessment is required.The role of endocrine risk reducing therapies in hereditary breast cancer is unclear. Tamoxifen and raloxifene reduce risk in high-risk women,88 89 though some groups caution against use in BRCA1 carriers due to high risk of triple-negative breast cancer.90 Emerging evidence shows possible benefit in BRCA1/2,91 92 but larger studies are required.In the context of women affected by breast cancer; our understanding of contralateral breast cancer risk and benefit of risk reducing surgery continues to evolve.93 While this is often considered for patients who have BRCA1/2 and TP53 variants, decision-making for those with variants in other CSGs remains more complex. Additionally, decisions regarding risk-reducing surgery must carefully balance multiple competing considerations, including the presence of an existing breast cancer diagnosis, the timing and implications of its treatment and the impact of concurrent comorbidities.Genetic findings increasingly inform treatment. Olaparib is recommended as adjuvant therapy for adults with germline BRCA1/2, HER2-negative, high-risk early breast cancer following chemotherapy.94 Evidence for use comes from the OlympiA trial which showed 1 year of adjuvant olaparib significantly improved outcomes for adults with germline BRCA1/2 mutated, HER2-negative high-risk early breast cancer, increasing 3-year invasive disease-free survival to 85.9% versus 77.1% with placebo.95Ovarian cancer Ovarian cancer remains notoriously difficult to detect early. The UKCTOCS trial demonstrated that surveillance did not result in earlier-stage diagnosis nor reduced mortality. 96 While NICE NG241 suggests surveillance using CA125 can be considered for patients with BRCA1, BRCA2, RAD51C, RAD51D, BRIP1 and PALB2 variants,97 this would sit in opposition to groups such as UK Cancer Genetics Group (UKCGG), who would not recommend this based on lack of evidence.86 90 98 It is worth noting that the NG241 guidance does caveat that surveillance should not be viewed as an alternative to risk-reducing surgery and is only an option for those who wish delay or not have surgery at all.96Risk-reducing bilateral salpingo-oophorectomy (RRBSO) is the primary prevention strategy for women at increased risk. NICE NG24196 advises offering RRBSO to women with a ≥5% lifetime risk, based on presence of a CSG and/or family history. Timing varies by gene: BRCA1 carriers generally undergo RRBSO no earlier than 35–40 years of age,90 BRCA2 no earlier than 40–45 years of age98 and BRIP1, PALB2, RAD51C, RAD51D around 50 years of age, guided by personalised risk assessment.86 In Lynch syndrome, RRBSO with hysterectomy is usually considered no earlier than 35–40 for those with MLH1, MSH2, MSH6 variants.99–101 PMS2 does not meet the 5% threshold for intervention.102RRBSO induces premature menopause, prompting interest in alternative strategies. The PROTECTOR study is evaluating staged risk-reduction via early salpingectomy followed by delayed oophorectomy. This UK multicentre trial includes premenopausal women with elevated genetic risk due to BRCA1, BRCA2, RAD51C, RAD51D, BRIP1, PALB2 or significant family history.103 Outcomes of the trial are awaited.Therapeutically, germline BRCA1/2 carriers with ovarian cancer may benefit from PARP inhibition, including olaparib.104Within the UK NICE guidance, NG241, recommends widening access to germline testing for individuals without cancer who have a family history of ovarian cancer. It advises offering testing when a person’s likelihood of carrying a pathogenic variant in an ovarian CSG is between 2% and 10%, with the threshold varying by age and sex.97 Roe et al105 highlight that implementing this guidance will require updates to the National Genomic Test Directory, careful resource planning, and ensuring equitable access across other hereditary cancer pathways.Colorectal cancer Lynch syndrome is one of the most well-recognised hereditary conditions associated with a significantly increased risk of colorectal cancer.In the UK, Lynch syndrome management follows a gene-specific approach. Colonoscopy for colorectal cancer prevention should start at age 25 for MLH1 and MSH2 carriers,99 100 and at age 35 for MSH6 and PMS2, with surveillance every 2 years.101 102 Although other cancer risks such as upper gastrointestinal, prostate and brain have been reported; routine screening for these sites are not implemented in the UK due to insufficient evidence.The protective effect of aspirin in reducing colorectal cancer risk among individuals with Lynch syndrome has been well established through the CAPP trials.106 107 Recent research has focused on optimising dose and duration.Additional surveillance, prevention and detection strategies A comprehensive discussion of management strategies for all CSGs and associated cancer risks is beyond the scope of this review. In the UK, the UKCGG has published numerous guidelines covering a range of CSGs, 108 while ERN GENTURIS109 is a European wide organisation that develops, co-authors, and endorses various guidelines.Cascade testing to relatives Once a pathogenic or likely pathogenic variant in a CSG has been identified, cascade testing can be offered to at-risk relatives. Cascade testing refers to the targeted genetic testing of family members for a previously identified familial variant. This process requires appropriate pre-test genetic counselling.The timing of testing often depends on the CSG involved. In most cases, testing aligns with the point at which surveillance and management strategies begin or when family planning is being considered. For most individuals this will be in early adulthood.Evans reviewed three decades of cascade screening for hereditary breast and ovarian cancer and Lynch syndrome.110 Between 1990 and 2020, the study reported substantial growth in family-based testing, with BRCA1/2 cases generating multiple additional tests and resulting in over 1000 risk-reducing surgeries.Reproductive decision-making As CSGs follow Mendelian patterns of inheritance there is a significant chance of passing it onto offspring, most commonly a 50% risk. For many families this is considered ‘much more than a gene’ and will include painful experiences such as cancer surveillance, illness, loss of relatives and disruptions to family life. 111Under the Human Fertilisation and Embryology Act 1990 (as amended in 2008), families affected by serious genetic conditions can prevent transmission to their children. The Act sets out licensing, inspection and compliance standards for procedures such as preimplantation genetic testing for monogenic disorders, which includes cancer susceptibility syndromes.112Moderate penetrance genes present unique challenges in reproductive decision-making. Risk prediction often lacks accuracy, and familial experience may not reflect reported penetrance. Guidance to support discussion was produced in 2023 in the UK.113Patient registries Patient registries are structured systems that collect long-term data on individuals with the same condition. They play a vital role in advancing research and improving healthcare outcomes, particularly for rare diseases.For many years patient registries were disease-specific and often relied on support from associated patient groups. An example would be the PTEN Hamartoma Tumour Syndrome Registry.114The English National Lynch Syndrome Registry marked one of the first standardised, nationwide approaches to patient registries. It was created to unify fragmented clinical and genomic data on Lynch syndrome across England and now supports national screening coordination, evaluation of NICE guidance, research and clinical trials, while offering insights into demographics, diagnosis timelines and outcomes.115The National Inherited Cancer Predisposition Registry is an initiative developed by National Disease Registration Service (NDRS) with NHS England and UKCGG. It builds on the work of the NDRS supported Lynch Registry. It captures data on individuals with pathogenic or likely pathogenic variants, enabling accurate prevalence figures, linkage to screening services and improved understanding of patient outcomes. The register supports research, clinical audit and centralised communication.116Conclusion The landscape of cancer genetics is expanding rapidly, reshaping how inherited cancer risk is identified, stratified, and managed across clinical practice.As understanding of monogenic, polygenic and multifactorial contributors to cancer risk continues to improve, traditional family history based approaches are being replaced by risk prediction models that combine genomic testing, tumour profiling and lifestyle assessment. This will allow more accurate stratification of cancer risk in any given individual.Improvements in testing technologies are transforming how germline and somatic variants are identified. Tumour-based sequencing now enables efficient detection of clinically actionable variants. ctDNA testing offers a less invasive alternative. As these technologies mature, they will increasingly support earlier detection and more accurate triage for germline follow-up.The shift toward population based genetic testing enables earlier identification of individuals at increased cancer risk allowing timely surveillance, prevention and interventions. Implementing broader testing requires sustainable service models, equitable access frameworks and robust multidisciplinary infrastructure to support interpretation, counselling and long-term management.