BRCA1 and BRCA2 – genetic testing

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

1. individuals with a combined BRCA1 and BRCA2 pathogenic variant probability of ≥10% using the Manchester score^r (a validated pathogenic variant prediction tool).
2. individuals with a combined BRCA1, BRCA2 and PALB2 pathogenic variant probability of ≥10% using CanRisk^r (a validated pathogenic variant prediction tool). This may include unaffected individuals and obligate carriers with ≥10% pathogenic variant probability as well as individuals from a population where a common founder pathogenic variant exists.
3. individuals affected with breast cancer:
   1. with triple negative pathology diagnosed ≤50 years
   2. with triple negative breast cancer diagnosed at any age where there is a close relative* with breast or ovarian^# cancer
   3. diagnosed ≤40 years
   4. male breast cancer diagnosed at any age.
4. individuals with high grade ovarian^# cancer diagnosed at any age.
5. males affected with prostate cancer who meet prostate cancer panel testing criteria.
6. individuals affected with pancreatic cancer who meet pancreatic cancer panel testing criteria.

Pathogenic variant specific BRCA1 or BRCA2 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 pathogenic variant has been identified.

*close relative = first or second degree relative
^#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. 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 frequency of heritable pathogenic variants in the BRCA1 and BRCA2 genes in unselected individuals with breast cancer is around 2%^r and with invasive ovarian cancer >14%^r in many ethnic groups.

Factors	Probability of detecting a heritable pathogenic variant
Outside of the pathogenic variant prediction scores, specific tumour features can inform the decision to offer testing:
Age ≤40 with invasive breast cancer	12%r 9.3% in non-TNBCr 24% in TNBCr
Triple negative breast cancer	11.2% (any age)r 16.5% (diagnosed <50 years)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
Ashkenazi Jewish ancestry	2.5%r 10% (any age and affected with breast cancer)r
Patient has a first or second degree relative with documented pathogenic variant	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.

A variant-specific test (rather than sequencing a single gene or gene panel) may be more cost effective and appropriate where: 

• a known pathogenic variant has been identified in a relative
• a specific pathogenic variant has been identified on somatic tumour testing. 

Predictive testing should never be ordered when only a variant of uncertain significance or benign/likely benign variant has been identified in a family.

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

• sequencing
• copy number analysis (e.g. MLPA).

Information about DNA tests and testing laboratories is available from:

• RCPA catalogue of genetic tests and laboratories
• GeneReviews^®
• European Directory of DNA Diagnostic Laboratories
• Genetic Testing Registry
• NHS National Genomic Test Directory

Where possible, BRCA1 and BRCA2 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 (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.

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 (e.g. MLPA, Sanger sequencing) should be considered in high risk families.

If genetic testing in DNA from peripheral blood is uninformative, testing of two or more different tumour samples may be indicated to assess for mosaicism.

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Bibliography

Antoniou, A. C., R. Hardy, L. Walker, et al. 2008. "Predicting the likelihood of carrying a BRCA1 or BRCA2 mutation: validation of BOADICEA, BRCAPRO, IBIS, Myriad and the Manchester scoring system using data from UK genetics clinics." J Med Genet 45(7):425-431.

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OBJECTIVES: Genetic testing for the breast and ovarian cancer susceptibility genes BRCA1 and BRCA2 has important implications for the clinical management of people found to carry a mutation. However, genetic testing is expensive and may be associated with adverse psychosocial effects. To provide a cost-efficient and clinically appropriate genetic counselling service, genetic testing should be targeted at those individuals most likely to carry pathogenic mutations. Several algorithms that predict the likelihood of carrying a BRCA1 or a BRCA2 mutation are currently used in clinical practice to identify such individuals. DESIGN: We evaluated the performance of the carrier prediction algorithms BOADICEA, BRCAPRO, IBIS, the Manchester scoring system and Myriad tables, using 1934 families seen in cancer genetics clinics in the UK in whom an index patient had been screened for BRCA1 and/or BRCA2 mutations. The models were evaluated for calibration, discrimination and accuracy of the predictions. RESULTS: Of the five algorithms, only BOADICEA predicted the overall observed number of mutations detected accurately (ie, was well calibrated). BOADICEA also provided the best discrimination, being significantly better (p <0.05) than all models except BRCAPRO (area under the receiver operating characteristic curve statistics: BOADICEA = 0.77, BRCAPRO = 0.76, IBIS = 0.74, Manchester = 0.75, Myriad = 0.72). All models underpredicted the number of BRCA1 and BRCA2 mutations in the low estimated risk category. CONCLUSIONS: Carrier prediction algorithms provide a rational basis for counselling individuals likely to carry BRCA1 or BRCA2 mutations. Their widespread use would improve equity of access and the cost-effectiveness of genetic testing.

Bansal, A., G. C. Critchfield, T. S. Frank, et al. 2000. "The predictive value of BRCA1 and BRCA2 mutation testing." Genet Test 4(1):45-48.

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Genetic testing for mutations in BRCA1 and BRCA2, two genes predisposing to breast and ovarian cancers, is available to women with a relevant family history. The aim of this study was to estimate the positive and negative predictive value of clinical sequence analysis of these genes. A reference graph showing positive and negative predictive values over a range of pre-test risk was derived, taking into account the sensitivity and specificity of a full-sequence analysis test. High positive and negative predictive values were found for women with pre-test risk between 4% and 40%, a range of risk commonly seen in clinical testing. The predictive value of full sequence and single-site analysis of BRCA1 and BRCA2, therefore, compares favorably with other diagnostic medical tests. Our results provide a numerical estimate of the predictive value of BRCA testing, and as such, provide a valuable tool to healthcare providers and families as they interpret BRCA1 and BRCA2 test results.

Berry, D. A., E. S. Iversen, Jr., D. F. Gudbjartsson, et al. 2002. "BRCAPRO validation, sensitivity of genetic testing of BRCA1/BRCA2, and prevalence of other breast cancer susceptibility genes." J Clin Oncol 20(11):2701-2712.

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PURPOSE: To compare genetic test results for deleterious mutations of BRCA1 and BRCA2 with estimated probabilities of carrying such mutations; to assess sensitivity of genetic testing; and to assess the relevance of other susceptibility genes in familial breast and ovarian cancer. PATIENTS AND METHODS: Data analyzed were from six high-risk genetic counseling clinics and concern individuals from families for which at least one member was tested for mutations at BRCA1 and BRCA2. Predictions of genetic predisposition to breast and ovarian cancer for 301 individuals were made using BRCAPRO, a statistical model and software using Mendelian genetics and Bayesian updating. Model predictions were compared with the results of genetic testing. RESULTS: Among the test individuals, 126 were Ashkenazi Jewish, three were male subjects, 243 had breast cancer, 49 had ovarian cancer, 34 were unaffected, and 139 tested positive for BRCA1 mutations and 29 for BRCA2 mutations. BRCAPRO performed well: for the 150 probands with the smallest BRCAPRO carrier probabilities (average, 29.0%), the proportion testing positive was 32.7%; for the 151 probands with the largest carrier probabilities (average, 95.2%), 78.8% tested positive. Genetic testing sensitivity was estimated to be at least 85%, with false-negatives including mutations of susceptibility genes heretofore unknown. CONCLUSION: BRCAPRO is an accurate counseling tool for determining the probability of carrying mutations of BRCA1 and BRCA2. Genetic testing for BRCA1 and BRCA2 is highly sensitive, missing an estimated 15% of mutations. In the populations studied, breast cancer susceptibility genes other than BRCA1 and BRCA2 either do not exist, are rare, or are associated with low disease penetrance.

Evans, D. G., M. Bulman, K. Young, et al. 2003. "Sensitivity of BRCA1/2 mutation testing in 466 breast/ovarian cancer families." J Med Genet 40(9):e107.

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no abstract available

Evans, D. G., A. Howell, D. Ward, et al. 2011. "Prevalence of BRCA1 and BRCA2 mutations in triple negative breast cancer." J Med Genet 48(8):520-522.

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Not available

Evans, D. G., F. Lalloo, A. Wallace, et al. 2005. "Update on the Manchester Scoring System for BRCA1 and BRCA2 testing." J Med Genet 42(7):e39.

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Abstract not available

Risch, H. A., J. R. McLaughlin, D. E. Cole, et al. 2006. "Population BRCA1 and BRCA2 mutation frequencies and cancer penetrances: a kin-cohort study in Ontario, Canada." J Natl Cancer Inst 98(23):1694-1706.

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BACKGROUND: BRCA1 and BRCA2 mutations in general populations and in various types of cancers have not been well characterized. We investigated the presence of these mutations in unselected patients with newly diagnosed incident ovarian cancer in Ontario, Canada, with respect to cancers reported among their relatives. METHODS: A population series of 1171 unselected patients with incident ovarian cancer diagnosed between January 1, 1995, and December 31, 1999, in Ontario, Canada, was screened for germline mutations throughout the BRCA1 and BRCA2 genes. Screening involved testing for common variants, then protein truncation testing of long exons, and then denaturing gradient gel electrophoresis or denaturing high-performance liquid chromatography for the remainder of BRCA1 and BRCA2, respectively. Cox regression analysis was used to examine cancer outcomes reported by the case probands for their 8680 first-degree relatives. Population allele frequencies and relative risks (RRs) were derived from the regression results by an extension of Saunders-Begg methods. Age-specific Ontario cancer incidence rates were used to estimate cumulative incidence of cancer to age 80 years by mutation status. RESULTS: Among 977 patients with invasive ovarian cancer, 75 had BRCA1 mutations and 54 had BRCA2 mutations, for a total mutation frequency of 13.2% (95% confidence interval [CI] = 11.2% to 15.5%). Higher risks for various cancer types in the general Ontario population were associated with BRCA1 mutation carriage than with noncarriage, including ovarian (RR = 21, 95% CI = 12 to 36), female breast (RR = 11, 95% CI = 7.5 to 15), and testis (RR = 17, 95% CI = 1.3 to 230) cancers. Higher risks were also associated with BRCA2 mutation carriage than with noncarriage, particularly for ovarian (RR = 7.0, 95% CI = 3.1 to 16), female and male breast (RR = 4.6, 95% CI = 2.7 to 7.8, and RR = 102, 95% CI = 9.9 to 1050, respectively), and pancreatic (RR = 6.6, 95% CI = 1.9 to 23) cancers. Cancer risks differed according to the mutation's position in the gene. Estimated cumulative incidence to age 80 years among women carrying BRCA1 mutations was 24% for ovarian cancer and 90% for breast cancer and among women carrying BRCA2 mutations was 8.4% for ovarian cancer and 41% for breast cancer. For the general Ontario population, estimated carrier frequencies of BRCA1 and BRCA2 mutations, respectively, were 0.32% (95% CI = 0.23% to 0.45%) and 0.69% (95% CI = 0.43% to 1.10%). CONCLUSIONS: BRCA1 and BRCA2 mutations may be more frequent in general populations than previously thought and may be associated with various types of cancers.

Young, S. R., R. T. Pilarski, T. Donenberg, et al. 2009. "The prevalence of BRCA1 mutations among young women with triple-negative breast cancer." BMC Cancer 9:86.

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BACKGROUND: Molecular screening for BRCA1 and BRCA2 mutations is now an established component of risk evaluation and management of familial breast cancer. Features of hereditary breast cancer include an early age-of-onset and over-representation of the 'triple-negative' phenotype (negative for estrogen-receptor, progesterone-receptor and HER2). The decision to offer genetic testing to a breast cancer patient is usually based on her family history, but in the absence of a family history of cancer, some women may qualify for testing based on the age-of-onset and/or the pathologic features of the breast cancer. METHODS: We studied 54 women who were diagnosed with high-grade, triple-negative invasive breast cancer at or before age 40. These women were selected for study because they had little or no family history of breast or ovarian cancer and they did not qualify for genetic testing using conventional family history criteria. BRCA1 screening was performed using a combination of fluorescent multiplexed-PCR analysis, BRCA1 exon-13 6 kb duplication screening, the protein truncation test (PTT) and fluorescent multiplexed denaturing gradient gel electrophoresis (DGGE). All coding exons of BRCA1 were screened. The two large exons of BRCA2 were also screened using PTT. All mutations were confirmed with direct sequencing. RESULTS: Five deleterious BRCA1 mutations and one deleterious BRCA2 mutation were identified in the 54 patients with early-onset, triple-negative breast cancer (11%). CONCLUSION: Women with early-onset triple-negative breast cancer are candidates for genetic testing for BRCA1, even in the absence of a family history of breast or ovarian cancer.

Zhang, S., R. Royer, S. Li, et al. 2011. "Frequencies of BRCA1 and BRCA2 mutations among 1,342 unselected patients with invasive ovarian cancer." Gynecol Oncol 121(2):353-357.

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BACKGROUND: The heritable fraction of ovarian cancer exceeds that of any other common adult cancer. Most inherited cases of ovarian cancer are due to a germline mutation in BRCA1 or BRCA2. It is important to have an accurate estimate of the proportion of ovarian cancer patients who carry a mutation and the specific factors which predict the presence of a mutation. METHODS: We tested a population-based series of 1342 unselected patients diagnosed with invasive ovarian cancer between 1995-1999 and 2002-2004 in Ontario, Canada, for germline mutations in BRCA1 and BRCA2. The two genes were tested in their entirety, using a range of techniques, including multiplex ligation-dependent probe amplification (MLPA). RESULTS: Among the 1342 women, 176 women carried a mutation (107 in BRCA1, 67 in BRCA2, and two in both genes) for a combined mutation frequency of 13.3%. Seven deletions were identified using MLPA (3.9% of all detected mutations). The prevalence of mutations was particularly high among women diagnosed in their forties (24.0%), in women with serous ovarian cancer (18.0%) and women of Italian (43.5%), Jewish (30.0%) or Indo-Pakistani origin (29.4%). A mutation was seen in 33.9% of women with a first-degree relative with breast or ovarian cancer and in 7.9% of women with no first-degree relative with breast or ovarian cancer. No mutation was seen in women with mucinous carcinoma. CONCLUSIONS: BRCA1 and BRCA2 mutations are common in women with invasive ovarian cancer. All women diagnosed with invasive non-mucinous ovarian cancer should be considered to be candidates for genetic testing.

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