1. Home
  2. Cancer genetics
  3. Adult
  4. Genetic testing for heritable pathogenic variants

BRCA1, BRCA2 and PALB2 (truncating variants) – genetic testing

In this document the terms ‘male’ and ‘female’ refer to sex assigned at birth. For more information about providing individualised care refer to Resources to assist in the care of transgender individuals referred to a clinical genetics service or familial cancer centre

eviQ cancer genetics consensus statement: scope of genetic testing protocols

On this page
Expand all Collapse all Back to top

Germline BRCA1, BRCA2 and PALB2 pathogenic variant search should be considered in the following situations:

  1. individuals with breast or ovarian cancer with a combined BRCA1 and BRCA2 pathogenic variant probability of ≥10% using the Manchester score (a validated pathogenic variant prediction tool).
  2. individuals with breast or ovarian cancer with a combined BRCA1, BRCA2 and PALB2 pathogenic variant probability of ≥10% using CanRisk (a validated pathogenic variant prediction tool). 
  3. individuals with breast cancer:
    1. diagnosed ≤40 yearsr
    2. bilateral breast cancer or 2 or more synchronous or asynchronous breast cancers with first cancer diagnosed age ≤50 yearsr
    3. with triple negative pathology diagnosed ≤60 yearsr or at any age if the individual would potentially be eligibile for adjuvant therapy with a PARP inhibitor
    4. hormone receptor positive, HER2 negative breast cancer and one or more high risk features (grade 3, lymph node positive, size >20mm), diagnosed at any age, if the individual would potentially be eligible for adjuvant therapy with a PARP inhibitor
    5. male breast cancer diagnosed at any age.
  4. individuals with high grade epithelial ovarian* cancer diagnosed at any age.
  5. individuals with prostate cancer who meet prostate cancer panel testing criteria.
  6. individuals with pancreatic cancer who meet pancreatic cancer panel testing criteria.
  7. individuals who are a first degree relative of deceased untested individuals with high grade epithelial ovarian cancer*r
  8. unaffected individuals and obligate carriers with a combined BRCA1, BRCA2 and PALB2 pathogenic variant probability of ≥10% using CanRisk (a validated pathogenic variant prediction tool). 

Pathogenic variant specific BRCA1, BRCA2 or PALB2 testing should be considered when there is:

  1. a pathogenic somatic variant detected on tumour testing for this individual.
  2. an individual with a personal and/or family history of breast, ovarian*, prostate or pancreatic cancer from a population where a common founder pathogenic variant exists who does not fulfil any of the criteria listed above.
  3. a familial BRCA1 or BRCA2 or PALB2 pathogenic variant has been identified.

* includes invasive, non-mucinous ovarian, fallopian tube and primary peritoneal cancer

Genetic testing is important for good clinical care of individuals who are suspected of having a heritable pathogenic variant in these genes. Where feasible genetic testing should first be offered to individuals in the family with the highest probability of a pathogenic variant. Panel testing including other high penetrance genes may be considered. The above criteria may include some individuals with lower than 10% likelihood of a pathogenic variant calculated by a structured algorithm, and the cost of genetic testing in such circumstances may not be covered by Medicare or the genetic service provider.

The results of the following investigations may significantly influence the likelihood of detecting a heritable pathogenic variant in the BRCA1, BRCA2 or PALB2 genes:

  • Verification of pathology for the affected individual offered genetic testing.
  • Verification of pathology for any suspected ovarian cancer (any reported gynaecological or abdominal cancer). BRCA1, BRCA2 and PALB2 are strongly associated with high grade serous epithelial pathology. 
  • Consideration of limited family structure or no knowledge of the family cancer history.
  • Calculation of likelihood of a BRCA1 or BRCA2 +/- PALB2 pathogenic variant using a validated risk model (e.g. Manchester score, CanRisk).
  • Previous genetic testing within the family.
  • Consideration of archival tumour testing for deceased, untested individuals with high grade epithelial ovarian cancer.r
  • Consideration of immunohistochemistry for MMR proteins MLH1, MSH2, MSH6 and PMS2 in ovarian tumours with endometrioid or clear cell histopathology and/or family history of colorectal, endometrial (Lynch syndrome-associated) cancers.
Factors Probability of detecting a heritable BRCA1 or BRCA2 pathogenic variant Probability of detecting a heritable PALB2 truncating pathogenic variant
Outside of the pathogenic variant prediction scores, specific tumour features can inform the decision to offer testing:
Unselected breast cancer

2%r

0.6%r
Age ≤40 years with invasive breast cancer

12%r

9.3% in non-TNBCr

24% in TNBCr

Increased

 

 
Triple negative breast cancer (TNBC)

11.2% (any age)r

11.4–16.8% (diagnosed age ≤60 years)rr

1.0–1.6%r

 
Male breast cancer

11%r

1.8%r
High grade (grades 2 & 3) invasive non-mucinous ovarian, fallopian tube or primary peritoneal cancer

15.3%r

9% (age ≤70 years with no family history)r

1%r

 
Ashkenazi Jewish ancestry

2.5%r

10% (any age and affected with breast cancer)r

N/A

 
Patient has a first or second degree relative with a documented pathogenic variant

Up to 50%

Up to 50%

Abbreviation: TNBC = triple-negative breast cancer

Genetic testing is not generally indicated outside these guidelines although needs to be considered on an individual basis.

Where the most appropriate person in the family has been tested and no pathogenic variant found, further BRCA testing is usually not required in the family.

Predictive testing should never be ordered for a variant of uncertain significance or a benign/likely benign variant.

A range of testing methodologies are needed to identify pathogenic changes in the BRCA 1, BRCA 2 or PALB2 genes including:

  • sequencing
  • copy number analysis.

Information about DNA tests and testing laboratories is available from:

Where possible, BRCA1, BRCA2 and PALB2 testing should be done as part of a panel test (refer to Breast cancer – panel testing, Ovarian cancer (epithelial) – panel testing, Pancreatic cancer – panel testing or Prostate cancer – panel testing). Clinical features and/or additional family history may guide choice of additional genes (e.g. CDH1, TP53, PTEN, MMR).

If a decision is made to test these genes as part of a cancer gene panel, care should be taken to select a panel where the individual genes tested have both clinical validity and clinical utility.

A variant-specific test (rather than sequencing a single gene or gene panel) may be more appropriate and cost effective where a relative is known to have a germline pathogenic variant or a pathogenic variant has been identified in the patient’s tumour.

If these genes are tested using genomic sequencing (“next generation sequencing” or NGS), and testing has not identified a pathogenic variant, the value of testing using another methodology should be considered in high risk families.

If genetic testing in DNA from peripheral blood does not identify a pathogenic variant, testing of other tumour and tissue samples may be indicated to assess for mosaicism.

Result Reference database Considerations and advice
Pathogenic variant search
Pathogenic variant

BRCA Exchange

ClinVar

LOVD
Variant of uncertain significance

Review pathogenicity of variants periodically

Identify other genes for which a pathogenic variant search could be considered 
No reportable variant  

Identify other genes for which a pathogenic variant search could be considered
Predictive testing
Family pathogenic variant identified  
Family pathogenic variant not found   Screening based on revised risk estimate

If a pathogenic variant is identified, refer to a clinical genetics service or familial cancer centre for review, family risk notification and predictive testing.

If a variant of uncertain significance is identified, consider referral to a clinical genetics service or familial cancer centre for review and guidance.

If a mosaic pathogenic variant is identified, refer to a clinical genetics service or familial cancer centre for review and guidance about the penetrance of phenotypic features (including cancer risk).

For additional information about the management of genetic test results when ordered by a non-genetic healthcare professional refer to eviQ’s Guide for health professionals ordering genetic testing.

[%id%]
[%title%]
[%abstract%]

Bibliography

Carver, T., S. Hartley, A. Lee, et al. 2021. "CanRisk Tool-A Web Interface for the Prediction of Breast and Ovarian Cancer Risk and the Likelihood of Carrying Genetic Pathogenic Variants." Cancer Epidemiol Biomarkers Prev 30(3): 469-473.

BACKGROUND: The CanRisk Tool (https://canrisk.org) is the next-generation web interface for the latest version of the BOADICEA (Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm) state-of-the-art risk model and a forthcoming ovarian cancer risk model. METHODS: The tool captures information on family history, rare pathogenic variants in cancer susceptibility genes, polygenic risk scores, lifestyle/hormonal/clinical features, and imaging risk factors to predict breast and ovarian cancer risks and estimate the probabilities of carrying pathogenic variants in certain genes. It was implemented using modern web frameworks, technologies, and web services to make it extensible and increase accessibility to researchers and third-party applications. The design of the graphical user interface was informed by feedback from health care professionals and a formal evaluation. RESULTS: This freely accessible tool was designed to be user friendly for clinicians and to boost acceptability in clinical settings. The tool incorporates a novel graphical pedigree builder to facilitate collection of the family history data required by risk calculations. CONCLUSIONS: The CanRisk Tool provides health care professionals and researchers with a user-friendly interface to carry out multifactorial breast and ovarian cancer risk predictions. It is the first freely accessible cancer risk prediction program to carry the CE marking. IMPACT: There have been over 3,100 account registrations, and 98,000 breast and ovarian cancer risk calculations have been run within the first 9 months of the CanRisk Tool launch.

Evans, D. G., E. F. Harkness, I. Plaskocinska, et al. 2017. "Pathology update to the Manchester Scoring System based on testing in over 4000 families." J Med Genet 54(10):674-681.

Version 14

Date Summary of changes
20/08/2024

The following sections of the document were updated by consensus of the reference committee chairs:

  • Target population:
    • Dot point "c" iii - added "..or at any age if the individual would potentially be eligibile for adjuvant therapy with a PARP inhibitor"
    • New dot point "c" iv - "hormone receptor positive, HER2 negative breast cancer and one or more high risk features (grade 3, lymph node positive, size >20mm), diagnosed at any age, if the individual would potentially be eligible for adjuvant therapy with a PARP inhibitor"
    • Removed "Genetic testing to guide therapeutic decisions is beyond the scope of this document. For individuals with lower than 10% likelihood of a pathogenic variant calculated by a structured algorithm, the cost of genetic testing in such circumstances may not be covered by Medicare."
  • Investigations before genetic testing:
    • Added "Consideration of archival tumour testing for deceased, untested individuals with high grade epithelial ovarian cancer"

Version increased to V.14. No change to review dates.

Version 13

Date Summary of changes
10/11/2023

Document reviewed at March 2023 cancer genetics reference committee meeting. Discussions continued via MS Teams and email. Approved for publication with the following changes made: 

  • Title: "PALB2 (truncating variants)" added to protocol title
  • Target population: criteria updated. Refer to PDF of previous version of protocol to compare changes
  • Investigations before testing: PALB2 added
  • Probability of a pathogenic variant:
    • PALB2 probability column added to table
    • "Unselected breast cancer" and "Male breast cancer" rows added to table
    • "Triple negative breast cancer (TNBC)" row - figure for BRCA1 or BRCA2 updated to "diagnosed age ≤ 60 years" to align with target population
  • Testing methods: template changes applied.

Version increased to V.13. Approved for publication on 30/10/2023. Published on 10/11/2023. Review in 2 years. 

Version 12

Date Summary of changes
23/11/2021

Target population discussed at the September 2021 reference committee meeting. Discussion continued via MS Teams. Approved for publication with the following changes made:

  • Target population
    •  Germline BRCA1 and BRCA2 pathogenic variant search... 
      • b. 'as well as individuals from a population where a common founder pathogenic variant exists.' added to end of sentence
      • c. added 'iv. male breast cancer diagnosed at any age'
    • Pathogenic variant specific BRCA1 or BRCA2 testing...
      • b. 'who does not fulfil any of the criteria listed above.' added to end of sentence

Version number increased to V.12.

Version 11

Date Summary of changes
11/08/2021

The following sections of the document were updated to align with a change made to the eviQ cancer genetics consensus statement: scope of genetic testing protocols document:

  • Target population: 
    • a. 'individuals with a combined BRCA1 and BRCA2 pathogenic variant probability of ≥10% using a validated pathogenic variant prediction tool (e.g. CanRisk or Manchester score). This may include unaffected individuals and obligate carriers with ≥10% pathogenic variant probability (note: using the CanRisk algorithm only)' split into two criteria with minor wording changes as follows:
      • 'a. individuals with a combined BRCA1 and BRCA2 pathogenic variant probability of ≥10% using the Manchester score (a validated pathogenic variant prediction tool)'
      • 'b. individuals with a combined BRCA1, BRCA2 and PALB2  pathogenic variant probability of ≥10% using CanRisk (a validated pathogenic variant prediction tool). This may include unaffected individuals and obligate carriers with ≥10% pathogenic variant probability.'
  • Investigations before genetic testing:
    • Fourth bullet: +/- PALB2 added
  • References: new reference added for CanRisk

Version number increased to V.11.
10/11/2021 Removed link to "European Directory of DNA Diagnostic Laboratories"

Version 10

Date Summary of changes
09/04/2021

The following sections of the document were updated to align with the publishing of the Ovarian cancer (epithelial) panel testing and Pancreatic cancer panel testing protocols: 

  • Related pages: added links to "Ovarian cancer (epithelial) panel testing" and "Pancreatic cancer panel testing"
  • Target population: added criterion e. "individuals affected with pancreatic cancer who meet pancreatic cancer panel testing  criteria" under "Germline BRCA1 and BRCA2 pathogenic variant search should be considered in the following situations:"
  • Testing methods: Ovarian cancer (epithelial) panel testing and Pancreatic cancer panel testing links added in the brackets of the following sentence: Where possible, BRCA1 and BRCA2 testing should be done as part of a panel test (refer to Breast cancer panel testing or Prostate cancer panel testing).

Version increased to V.10.

Version 9

Date Summary of changes
09/12/2020

The following sections of the document were updated to align with the new eviQ cancer genetics genetic testing template:

  • Related pages: added links to "Guide for health professionals ordering genetic testing" and "Cancer predisposition genes: population carrier frequency". Removed link to "Pre-test counselling"
  • Circumstances in which testing is not indicated: template wording updated
  • Testing methods: template wording updated
  • Result interpretation: template sentences added (including link to "Guide for health professionals ordering genetic testing")
  • Counselling: section deleted
  • Version number increased to V.9. 

Version 8

Date Summary of changes
02/07/2020

Protocol reviewed at October 2019 eviQ cancer genetics reference committee meeting and discussions continued via email. Approved for publication with the following changes made:

  • Target population: Criteria reviewed and refined. Separated into two subsections for clarity - "Germline BRCA1 and BRCA2 testing" and "Pathogenic variant specific BRCA1 and BRCA2 testing"
    • Germline BRCA1 and BRCA2 pathogenic variant search should be considered in the following situations
      • Part a: validated pathogenic variant prediction tool BOADICEA replaced by CanRisk. BRCAPRO removed as no longer used.
      • Part b: "Individuals affected with breast cancer: diagnosed ≤40 years" added
      • Part c: ovarian cancer criteria changed to "Individuals with high grade ovarian cancer diagnosed at any age" with footnote "includes invasive, non-mucinous ovarian, fallopian tube and primary peritoneal cancer" (in previous version, criteria was age ≤70 years)
      • Part d: added "Males affected with prostate cancer who meet Prostate cancer panel testing criteria"
    • Pathogenic variant specific BRCA1 or BRCA2 testing should be considered when there is:
      • Part b: "a personal and/or family history of breast and/or ovarian cancer, from a population where a common founder mutation exists" changed to "a personal and/or family history of breast, ovarian, prostate or pancreatic cancer from a population where a common founder mutation exists."
    • The following criterion was removed from the target population due to lack of evidence: "Where there is limited family structure or no knowledge of family cancer history...". Consideration of limited family structure or no knowledge of family history added to "Investigations before genetic testing"
    • Added sentence: "The above criteria may include some individuals with lower than 10% likelihood of a pathogenic variant calculated by a structured algorithm, and the cost of genetic testing in such circumstances may not be covered by Medicare or the genetic service provider."
  • Investigations before genetic testing: 6 bullet points added
  • Probability of a heritable pathogenic variant: Table updated. Factors and probabilities added with references, to align with some of the inclusion criteria in the target population
  • Testing methods: Paragraph added: "Where possible, BRCA1 and BRCA2 testing should be done as part of a panel test (refer to Breast cancer panel testing protocol or Prostate cancer panel testing protocol). Clinical features and/or additional family history may guide choice of additional genes (CDH1, TP53, PTEN, MMR)."
  • Result interpretation: reference databases reviewed. BRCA Exchange and Insight added to list
  • Protocol template changes applied
  • "Mutation" changed to "pathogenic variant" and "unclassified variant" changed to "variant of uncertain significance"  throughout document for consistency among eviQ cancer genetics protocols per agreement among the cancer genetics reference committees' chairs. Definition of "pathogenic variant" added as a pop-up

Version number increased to V.8. Review again in 2 years.
25/08/2020

Minor wording change in Target population section:

b. Individuals affected with breast cancer:
    i. with triple negative pathology diagnosed ≤50 years OR where there is a close relative* with breast or ovarian# cancer 
    ii. with breast cancer diagnosed ≤40 years

changed to 

b. Individuals affected with breast cancer:
    i. with triple negative pathology diagnosed ≤50 years
    ii. with triple negative breast cancer diagnosed at any age where there is a close relative* with breast or ovarian# cancer
    iii. diagnosed ≤40 years

Version 7

Date Summary of changes
13/08/2010 Published
28/02/2011 Target population and investigations which should be considered before germline testing updated as per consensus of reference committee.
07/03/2011 Combined Manchester Score changed from 15 to 16 as per reference committee feedback.
05/09/2011

Reviewed at RC meeting - Target population updated. Circumstances in which testing is not indicated amended to include considering testing outside these guidelines on an individual basis and where the most appropriate person in the family has been tested and no mutation found, further testing is not required.

Ages in target population changed to less than or equal to to align with the references.
15/02/2012

Discussed at national reference committee meeting October 2011 and following changes made under:

Target Population "high grade serous or endometroid ovarian" changed to "high grade invasive non-mucinous ovarian"

Added "where a known pathogenic mutation has been identified in a relative"

Factors which influence the pre-test probability of a germline mutation 
Factor:
Tumour features may be included in decision to test:

  • young (< 41 yrs) triple negative breast cancer (+/- basal markers)
  • invasive ovarian < 60 yrs

changed to
Tumour features can inform the decison to test:

  • young (< 41 yrs) triple negative breast cancer (+/- basal markers) without family history  
  • invasive ovarian cancer <60 yrs (all subtypes)

Minor additions to clarify Diagnostic and Predictive testing sections

Reference list updated
Berry D.A. et al 2002 and Risch, H.A. et al 2006 moved to history tab
James, P.A. et al 2006 and Zhang, S. et al 2011 added to reference list
04/07/2013

Discussed at national reference committee meeting March 2013  and the following changes made: 

All protocol headings updated according to new template.

Target Population - reformatted and updated 

  • with high grade invasive non-mucinous ovarian, fallopian tube or primary peritoneal cancer < age 60 yrs changed to
  • with an isolated high grade (Grades 2 & 3) invasive non-mucinous ovarian, fallopian tube or primary peritoneal cancer < age 70 yrs.
  • with invasive non-mucinous ovarian, fallopian tube or primary peritoneal cancer at any age and a family history* of breast or ovarian cancer - added 

Investigations which should be considered before germline genetic testing - updated.

Factors which influence the pre-test probablity of a heritable mutation - updated.

Diagnostic testing - table updated.

Interpretation of mutation testing results - table updated.

Website resources - updated.

Reference list - updated
Zhang, S., R. Royer, S. Li, et al. 2011 and  Evans, D. G., A. Howell, D. Ward, et al. 2011 moved to history tab.
Alsop, K et al 2012 and Hartman, A.R. et al 2012 added to reference list.
26/03/2014

Following discussion at March 5 2014 reference committee meeting the following change has been made:

  • Diagnostic testing - Link to Human Genetics Society of Australasia removed.
01/05/2014

Following discussion of the NICE clinical guideline 164 - Familial breast cancer in relation to eviQ protocols at the October 30 2013 & 5 March 2014 reference committee meetings and further email discussion, the following recommendation has been added to the Target population:

  • where local resources allow, if there is no affected relative available for testing, consider testing an unaffected individual with a calculated BRCA1/2 mutation probability of 20% or more using a BRCA1/2 mutation probability risk calculator e.g. BOADICEA.**
     

    **This is a new recommendation for review in 12 months

 Recommendation and protocol to be reviewed in 12 months
30/09/2015 Sentence added to Genetic Testing protocol template: if a decision is made to test this gene(s) as part of a cancer gene panel, care should be taken to select a panel where the individual genes tested have both clinical validity and clinical utility.
02/03/2016

Reviewed at May 2015 reference committee meeting and discussions continued via email. The following changes made:

  • target population - updated, including addition of 'limited family structure' and age for individuals with triple negative breast cancer changed from <40 years to <50 years
  • diagnostic testing - updated according to new template 
  • for yearly review.
10/03/2017

Based on changes to MBS criteria for BRCA1/2 testing (and it now having an MBS item number), protocol amended to reflect change:

  • target population - 'based on ovarian cancer characteristics' updated

Protocol to undergo full review in May 2017 as planned.
31/05/2017 Transferred to new eviQ website. Version number changed to V.5.
01/06/2018 Removed four links to the Clinical molecular genetics society best practice guidelines (CMGS) in Result Interpretation section, as webpage no longer available.
14/06/2018

Protocol reviewed and presented at the November 2017 eviQ reference committee meeting. Discussion continued over email and document approved for publication with the following changes: 

  • Target population:
    • 2. a. i – ‘breast or ovarian’ changed to ‘breast and/or ovarian'
    • 2. a. iii - 'where local resources allow, and' removed from beginning of sentence.
    • 2. c. ii – ‘relapsed’ added after ‘invasive’
    • 2. c. iii - (i.e. relapsed ovarian cancer) added to end of bullet point.
    • 3. 'limited family structure' changed to 'limited family structure or no knowledge of the family cancer history'
    • Added '3. c. triple negative breast cancer under the age of 60'
  • Testing methods:
    • Gene Tests link renamed as GeneReviews
  • Website resources:
    • Further references section removed - references listed in History tab moved to front of protocol in the Bibliography section.
  • Reference list updated to include Bibliography.
28/08/2019 Protocol title changed from 'Genetic testing for heritable mutations in the BRCA1 and BRCA2 genes' to 'BRCA1 and BRCA2 genetic testing' in accordance with Cancer Genetics Reference Committees' consensus. Version number increased to V.7

The information contained in this document is based on the highest level of available evidence and consensus of the eviQ reference committee regarding their views of currently accepted approaches to care or treatment. Any clinician seeking to apply or consult this document is expected to use independent clinical judgement in the context of individual clinical circumstances to determine any patient's care or treatment. While eviQ endeavours to link to reliable sources that provide accurate information, eviQ and the Cancer Institute NSW do not endorse or accept responsibility for the accuracy, currency, reliability or correctness of the content of linked external information sources. Use is subject to eviQ’s disclaimer available at www.eviQ.org.au

Send feedback for this page

First approved:
Last reviewed:
Review due:

The currency of this information is guaranteed only up until the date of printing, for any updates please check:

https://www.eviq.org.au/p/620

11 Oct 2024