The offer of a gene panel test should be considered for individuals diagnosed with a cancer that meet one or more of the following criteria. 

Eligibility Criteria: 

Patient diagnosed with 

• Breast cancer under age 40
• Bilateral breast cancer, both under age 60
• Triple negative breast cancer (TNBC), under age 60
• Breast cancer under age 45 with (at least) one 1st degree relative under age 45
• Breast cancer AND ovarian cancer, any age
• Male breast cancer, any age
• Breast cancer AND 10% or more probability of a germline pathogenic/likely pathogenic variant based on CanRisk (all genes) or a Manchester score of 15 or more.

Genes to be tested

Breast panel:BRCA1, BRCA2, TP53, PALB2, PTEN, STK11, ATM, CHEK2, RAD51C and RAD51D. CDH1 is not included in the panel however can be added when appropriate eligibility criteria* met.

*CDH1 criteria for testing:

• Lobular breast cancer and diffuse gastric cancer (both <70 years)
• Bilateral or multiple ipsilateral lobular breast cancer <50 years
• Lobular breast cancer <70 years plus≥1 FDR/SDR with diffuse gastric cancer at any age
• Lobular breast cancer and ≥FDR/SDR has diffuse gastric cancer (≥ 1 case occurred < 70 years).

Eligibility for testing in individuals affected with other cancers such as ovarian, prostate or pancreatic cancers: please refer to the Scottish Genomic Test Directory for eligibility criteria and appropriate panel details.

Types of Testing

• Treatment Focused Testing: Testing in patients to inform treatment or follow up may be undertaken by a Registered Healthcare professional involved in the patient’s care, following local protocols. Testing is generally restricted to breast surgery and oncology teams taking consent. If eligibility is uncertain, the patient can be referred to the Genetic Services for assessment of eligibility or additional discussion. All patients with a clinically significant variant should be referred to Genetic Services for appropriate counselling and support.

• Testing for a person with no personal history of breast cancer but with an available affected relative who meets the criteria for testing: The person with no personal history of cancer should be advised to ask their relative to seek testing (via their own cancer service or via their local genetic services). If it is not possible to test a living affected relative, it may be possible for testing to be carried out in a deceased relative affected with breast or ovarian cancer, if there is
  • A tissue sample available for DNA extraction, AND 
  • Pathology-adjusted Manchester score ≥17 or CanRisk score ≥15%, AND 
  • No living affected individual is available for genetic testing 

• Testing for a person with a family history, but no personal history, of breast / ovarian cancer and no available affected relative to test (unaffected testing): Genetic testing can be offered by clinical genetics to an unaffected individual if their Manchester score is ≥19 , or their probability of germline pathogenic/likely pathogenic variant on CanRisk is ≥10%.

• Testing for a person with a known pathogenic/likely pathogenic variant in the family: If a pathogenic or likely pathogenic variant is identified in an individual, then relatives also at risk of inheriting the variant can be offered testing regardless of whether they have had cancer or not. The Clinical Genetics team cascades and undertakes the offer of predictive testing to at-risk relatives.

Assessing Risk following Genetic Testing

The following outcomes of germline testing will confer a very high risk (>40% lifetime risk) of breast cancer in females

• Heterozygous pathogenic/likely pathogenic variants in BRCA1, BRCA2, TP53, PALB2, STK11,PTEN and CDH1. 
• Heterozygous c.7271T>G variant in ATM
• Homozygous or compound heterozygous pathogenic/likely pathogenic variants in ATM and CHEK2.

Heterozygous pathogenic/likely pathogenic variants in ATM, CHEK2, RAD51C and RAD51D are generally considered to confer a moderately increased risk (lifetime risk between 17-30%). However, an individualised risk assessment using CanRisk should be completed to factor in both genetic test results and family history.

Radiation Contraindications

Radiation is contraindicated in individuals with ATM homozygote (or compound heterozygote) or TP53 heterozygote pathogenic/likely pathogenic variants.

*Female being used to refer to those assigned female at birth and who have not had any masculising or gender affirming treatments. Any patients who have had such treatment would need personalised risk assessment.

Family History 

Females being considered for enhanced screening based on family history should be referred to a family history clinic for assessment of risk and need for family-based hereditary cancer gene panel testing.

Confirmation of Family History  

For accurate risk estimation, the following are required: 

• age of diagnosis of affected relatives and cancer site and type.
• current age or age of death of unaffected close relatives. 

Confirmation of relatives’ cancer diagnosis using medical records, cancer registry or death certificates should be performed for abdominal malignancies wherever possible. In general, it is not necessary to validate breast cancer-only histories. However, when substantial management decisions, i.e. risk-reducing surgery, are being considered and no causative variant has been identified, breast cancer history should be verified. Where no family history verification is possible, agreement by a multidisciplinary team should be sought before proceeding with risk-reducing surgery. 

Females affected with breast cancer and a family history 

Following discharge from cancer services, females affected with breast cancer, who are either not eligible for genetic testing or who have not been found to carry a pathogenic/likely pathogenic variant on testing, should receive surveillance equivalent to those with the same family history but without a personal history of breast cancer.

Very high risk: gene carrier

High risk

Moderate risk

Low risk

*A first-degree relative is mother, father, daughter, son, sister or brother. A second-degree relative is grandmother, grandfather, granddaughter, grandson, aunt, uncle, niece, nephew, half-sister or half-brother.

Very high risk 

• Heterozygous carrier of a pathogenic/likely pathogenic variant in BRCA1, BRCA2, PALB2, STK11, PTEN and CDH1.
• Heterozygous carrier of c.7271T>G ATM
• Homozygous pathogenic/likely pathogenic variants in ATM, CHEK2
• Female with a lifetime risk of developing breast cancer of 40% or more (see category definitions)

*To qualify for screening under 30 years female must be a BRCA1, BRCA2 or PALB2 carrier AND have an 8% or greater 10 year risk at the age when entered.

**Continue with MRI screening only if significant breast density persists.

Very high risk: TP53 Carriers

Very high risk: A-T homozygotes 

Untested females with 50% or greater risk of a pathogenic/likely pathogenic variant in a high-risk gene

• Very High Risk protocol up to age 50 when this should be reviewed.
• If the female remains untested after age 50 years, they move to the High Risk protocol.

High risk 

• Equates to a lifetime risk of developing breast cancer of 30% or more, or greater than 8% 10-year risk between 40 and 50 years of age

*Screening starts at 35 years or 5 years earlier than the youngest age of onset in the family (but not before 30 years) 

Moderate risk 

• Equates to a lifetime risk of breast cancer of greater than 17% but less than 30%   or 

• a 10-year risk between 40 and 50 years of age which is greater than 3% but less than 8%

*Screening starts at 40 years or 5 years earlier than the youngest age of onset in the family (but not before 35 years)

Low risk

Screening age 71 or over

Women age 71 or over no longer receive breast screening invitations from the National Breast Screening programme but can self-refer for breast screening every 3 years. Women assessed to be very high risk will continue to receive invites for annual screening.  

Printable version of Risk Category and Screening Protocols Summary

Recommendations for all females having surveillance 

• All screening mammography should be digital and performed at centres providing mammography to national breast screening programme standards.
• Ensure that individual strategies are developed for all females having mammographic surveillance and that surveillance is:
  • to national breast screening programme standards
  • audited
  • only undertaken after written information is given about risks and benefits.
• Ensure that MRI surveillance includes MRI of both breasts performed to national breast screening programme standards.
• Ensure a robust recall system is in place equivalent to national breast screening programme.

Risk reducing bilateral mastectomy is appropriate only for a small proportion of females from high risk families and should be managed by a multidisciplinary team. Any patients considering risk reducing surgery because of an increased familial risk should have had their risk assessed recently by Clinical Genetics and have access to Clinical Psychology.

Females affected with breast cancer 

Contralateral mastectomy is not generally advised for those with unilateral cancer due to doubling of risks with no survival benefit. However, where there is increased risk of contralateral cancer conferring a remaining lifetime risk of breast cancer of 30% or greater, it can be considered.

 The risks and benefits of risk-reducing contralateral mastectomy should be discussed with females undergoing breast cancer treatment with at least one of the following:

• A known pathogenic / likely pathogenic variant conferring a 30% or greater (high or very high) risk of contralateral breast cancer.
• A family history of breast cancer estimated to confer a 30% or greater (high or very high) remaining lifetime risk of contralateral breast cancer, with all breast cancer diagnoses confirmed in the family where possible*.

For patients with an active cancer who are deemed at Very High risk of further breast cancers due to a pathogenic or likely pathogenic gene variant, the treatment of the cancer may outweigh the need for Clinical Genetics review. However, involvement from Clinical Genetics should be offered to the patient whenever feasible. It should always be confirmed that the patient's genetic testing has been undertaken by a UKAS (or equivalent) accredited laboratory prior to surgery. 

Females with no personal history of breast cancer 

Prophylactic bilateral risk reducing mastectomy can be considered for females estimated to have a high (> 30%) or very high (> 40%) lifetime risk of breast cancer (see above).

The risks and benefits of prophylactic bilateral mastectomy should be discussed with females with at least one of the following:

• A known pathogenic/likely pathogenic variant conferring a 30% or greater (high or very high) remaining lifetime risk of breast cancer.
• A family history of breast cancer estimated to confer a 30% or greater remaining lifetime risk of breast cancer, with all breast cancer diagnoses confirmed in the family where possible*.

*Where no family history verification is possible, bilateral risk reducing mastectomy should only be considered if there is agreement by a multidisciplinary team including Clinical Genetics, Breast Surgery and Clinical Psychology.

• Discuss the risks and benefits of risk-reducing bilateral salpingo-oophorectomy with females with a known pathogenic/likely pathogenic variant in a gene known to increase the risk of ovarian cancer or a family history assessed to increase the risk of ovarian cancer by 5% or more. 

• Include in the discussion the positive effects of reducing the risk of ovarian (and in some cases breast cancer) and the negative effects of a surgically induced menopause. 
• Defer risk-reducing bilateral salpingo-oophorectomy until females have completed their family. 

Contraindications to risk-reducing surgery

• Do not offer risk-reducing surgery to people with comorbidities that would considerably increase the risks of surgery. 
• Do not offer risk-reducing surgery to people who have a limited life expectancy from their cancer or other conditions. 

Some high-risk pathogenic/likely pathogenic variant carriers (both female and male) might consider the option of Preimplantation Genetic Testing (PGT) to avoid passing the variant onto their children. PGT is a process that involves ‘in vitro fertilisation’ (IVF) to create embryos from the couple in the laboratory, which are then tested at an early stage for the familial variant.  Access to PGT is through the Clinical Genetics Service and only where PGT eligibility criteria are met.

In 2018 the Association of British Insurers agreed to an open-ended moratorium which means unaffected carriers of a pathogenic/likely pathogenic variant will not have to disclose the results of their predictive genetic test if taking out life or critical illness insurance after genetic testing.  The Moratorium will be reviewed by the Department of Health and the ABI every 3 years. 

Those who are having genetic testing as part of their diagnostic process (e.g. a breast cancer patient) would be having a diagnostic genetic test. Insurers can use this to inform subsequent applications for life or critical illness insurance. However, the key element of insurance evaluation is likely to be a cancer diagnosis, rather than at-risk status. 

UKCGG management guidelines for gene carriers 

The UK Cancer Genetic Group have developed guidelines for the following gene carriers

• BRCA1 
• BRCA2
• PTEN
• PALB2

Horizon scanning 

• Consider screening for mod risk age 50 – 60 – SEE NICE Guidelines

References 

1. NICE CG164 Familial breast cancer: Classification and care of people at risk of familial breast cancer and management of breast cancer and related risks in people with a family history of breast cancer Issued: June 2013
2. PHE Protocols for surveillance of women at very high risk of developing breast cancer - GOV.UK (www.gov.uk)
3. PHE Tests and frequency of testing for women at very high risk - GOV.UK (www.gov.uk)
4. HIS Familial breast cancer report (healthcareimprovementscotland.org)
5. UK Cancer Genetics Group (2018) Consensus for genes to be included on cancer panel tests offered by UK genetics services. Authors: Amy Taylor,1 Angela F Brady,2 Ian M Frayling,3,4 Helen Hanson,5 Marc Tischkowitz,1,6 Clare Turnbull,7,8,9 Lucy Side,10 on behalf of the UK Cancer Genetics Group (UK-CGG) 
6. The Manchester Scoring System (MSS) allows the calculation of the probability for the presence of a pathogenic variant in the BRCA1 and BRCA2 genes in families suspected of having hereditary breast and ovarian cancer.  (Evans et al, 2004)
7. Reference: Evans DG et al, 2017.  Pathology update to the Manchester Scoring System based on testing in over 4000 families. J Med Genet 54: 674-681

Appendices

1. Manchester Scoring System