No evidence that protein truncating variants inBRIP1are associated with breast cancer risk: implications for gene panel testing

"Breast cancer affects more than 360,000 women per year in the EU and causes more than 90,000 deaths. Identification of women at high risk of the disease can lead to early detection or disease prevention through intensive screening, therapeutic and/or lifestyle preventive measures, or prophylactic surgery. Breast cancer risk is determined by a combination of genetic and lifestyle risk factors. The advent of next generation sequencing has opened the opportunity for testing in many disease genes, and diagnostic gene panel testing is being introduced in many EU countries. However, the cancer risks associated with most variants in most genes are unknown. This leads to a major problem in appropriate counselling and management of women undergoing panel testing. The BRIDGES and B-CAST projects are jointly building a knowledge base that will allow identification of women at high-risk of specific subtypes of breast cancer, through comprehensive evaluation of DNA variants in known and suspected breast cancer genes. The effort exploits the huge resources established through the Breast Cancer Association Consortium (BCAC) and ENIGMA (Evidence-based Network for the Interpretation of Germline Mutant Alleles). Existing datasets will be expanded by sequencing all known breast cancer susceptibility genes in >100,000 breast cancer cases and controls from population-based studies. Risk factor and tumour genome data have been collected for 10,000 cases. Jointly, the data will allow us to generate a comprehensive risk model with unprecedented discriminative power, that can provide personalised risk estimates. We will develop online tools to aid the interpretation of gene variants and provide risk estimates in a user-friendly format, to help genetic counsellors and patients worldwide to make informed clinical decisions for risk management. We will evaluate the acceptability and utility of comprehensive gene panel testing in the clinical genetics context."

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Abstract PS7-04: Population-based estimates of breast cancer risk for germline pathogenic variants identified by gene-panel testing: An Australian perspective

10.1158/1538-7445.sabcs20-ps7-04 ◽

2021 ◽

Author(s):

Tu Nguyen-Dumont ◽

James Dowty ◽

Katherine Tucker ◽

Judy Kirk ◽

Paul James ◽

...

Keyword(s):

Breast Cancer ◽

Breast Cancer Risk ◽

Cancer Risk ◽

Population Based ◽

Gene Panel ◽

Panel Testing ◽

Pathogenic Variants ◽

Gene Panel Testing

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Population-based estimates of breast cancer risk for carriers of pathogenic variants identified by gene-panel testing

npj Breast Cancer ◽

10.1038/s41523-021-00360-3 ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Melissa C. Southey ◽

James G. Dowty ◽

Moeen Riaz ◽

Jason A. Steen ◽

Anne-Laure Renault ◽

...

Keyword(s):

Breast Cancer ◽

Breast Cancer Risk ◽

Cancer Risk ◽

Population Based ◽

Cancer Predisposition ◽

Gene Panel ◽

Breast Cancer Predisposition ◽

Panel Testing ◽

Pathogenic Variants ◽

Gene Panel Testing

AbstractPopulation-based estimates of breast cancer risk for carriers of pathogenic variants identified by gene-panel testing are urgently required. Most prior research has been based on women selected for high-risk features and more data is needed to make inference about breast cancer risk for women unselected for family history, an important consideration of population screening. We tested 1464 women diagnosed with breast cancer and 862 age-matched controls participating in the Australian Breast Cancer Family Study (ABCFS), and 6549 healthy, older Australian women enroled in the ASPirin in Reducing Events in the Elderly (ASPREE) study for rare germline variants using a 24-gene-panel. Odds ratios (ORs) were estimated using unconditional logistic regression adjusted for age and other potential confounders. We identified pathogenic variants in 11.1% of the ABCFS cases, 3.7% of the ABCFS controls and 2.2% of the ASPREE (control) participants. The estimated breast cancer OR [95% confidence interval] was 5.3 [2.1–16.2] for BRCA1, 4.0 [1.9–9.1] for BRCA2, 3.4 [1.4–8.4] for ATM and 4.3 [1.0–17.0] for PALB2. Our findings provide a population-based perspective to gene-panel testing for breast cancer predisposition and opportunities to improve predictors for identifying women who carry pathogenic variants in breast cancer predisposition genes.

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Extended gene panel testing in lobular breast cancer

Familial Cancer ◽

10.1007/s10689-021-00241-5 ◽

2021 ◽

Author(s):

Elke M. van Veen ◽

D. Gareth Evans ◽

Elaine F. Harkness ◽

Helen J. Byers ◽

Jamie M. Ellingford ◽

...

Keyword(s):

Breast Cancer ◽

Genetic Testing ◽

Detection Rate ◽

Gene Panel ◽

Lobular Breast Cancer ◽

Germline Variants ◽

Panel Testing ◽

Pathogenic Variants ◽

Gene Panel Testing ◽

Increased Risk

AbstractPurpose: Lobular breast cancer (LBC) accounts for ~ 15% of breast cancer. Here, we studied the frequency of pathogenic germline variants (PGVs) in an extended panel of genes in women affected with LBC. Methods: 302 women with LBC and 1567 without breast cancer were tested for BRCA1/2 PGVs. A subset of 134 LBC affected women who tested negative for BRCA1/2 PGVs underwent extended screening, including: ATM, CDH1, CHEK2, NBN, PALB2, PTEN, RAD50, RAD51D, and TP53.Results: 35 PGVs were identified in the group with LBC, of which 22 were in BRCA1/2. Ten actionable PGVs were identified in additional genes (ATM(4), CDH1(1), CHEK2(1), PALB2(2) and TP53(2)). Overall, PGVs in three genes conferred a significant increased risk for LBC. Odds ratios (ORs) were: BRCA1: OR = 13.17 (95%CI 2.83–66.38; P = 0.0017), BRCA2: OR = 10.33 (95%CI 4.58–23.95; P < 0.0001); and ATM: OR = 8.01 (95%CI 2.52–29.92; P = 0.0053). We did not detect an increased risk of LBC for PALB2, CDH1 or CHEK2. Conclusion: The overall PGV detection rate was 11.59%, with similar rates of BRCA1/2 (7.28%) PGVs as for other actionable PGVs (7.46%), indicating a benefit for extended panel genetic testing in LBC. We also report a previously unrecognised association of pathogenic variants in ATM with LBC.

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Gene-Panel Sequencing and the Prediction of Breast-Cancer Risk

New England Journal of Medicine ◽

10.1056/nejmsr1501341 ◽

2015 ◽

Vol 372 (23) ◽

pp. 2243-2257 ◽

Cited By ~ 468

Author(s):

Douglas F. Easton ◽

Paul D.P. Pharoah ◽

Antonis C. Antoniou ◽

Marc Tischkowitz ◽

Sean V. Tavtigian ◽

...

Keyword(s):

Breast Cancer ◽

Breast Cancer Risk ◽

Cancer Risk ◽

Gene Panel ◽

Gene Panel Sequencing ◽

Panel Sequencing

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167P Role of the multi-gene panel testing for detection of pathogenic variants in patients with hereditary bilateral breast cancer

Annals of Oncology ◽

10.1016/j.annonc.2021.08.448 ◽

2021 ◽

Vol 32 ◽

pp. S432-S433

Author(s):

C. Filorizzo ◽

D. Fanale ◽

L. Incorvaia ◽

N. Barraco ◽

M. Bono ◽

...

Keyword(s):

Breast Cancer ◽

Bilateral Breast Cancer ◽

Gene Panel ◽

Panel Testing ◽

Pathogenic Variants ◽

Gene Panel Testing

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Multi gene panel testing for hereditary breast cancer - is it ready to be used?

Medicine and Pharmacy Reports ◽

10.15386/mpr-1083 ◽

2019 ◽

Cited By ~ 1

Author(s):

Andreea Catana ◽

Adina Patricia Apostu ◽

Razvan-Geo Antemie

Keyword(s):

Breast Cancer ◽

Hereditary Breast Cancer ◽

Gene Panel ◽

Variants Of Uncertain Significance ◽

Panel Testing ◽

Brca Genes ◽

Prophylactic Measures ◽

Gene Panel Testing ◽

Uncertain Significance ◽

High Level

Breast cancer is one of the most common malignancies and the leading cause of death among women worldwide. About 20% of breast cancers are hereditary. Approximately 30% of the mutations have remained negative after testing BRCA1/2 even in families with a Mendelian inheritance pattern for breast cancer. Additional non-BRCA genes have been identified as predisposing for breast cancer. Multi gene panel testing tries to cover and explain the BRCA negative inherited breast cancer, improving efficiency, speed and costs of the breast cancer screening. We identified 23 studies reporting results from individuals who have undergone multi gene panel testing for hereditary breast cancer and noticed a prevalence of 1-12% of non-BRCA genes, but also a high level of variants of uncertain significance. A result with a high level of variants of uncertain significance is likely to be more costly than bring benefits, as well as increase the anxiety for patients. Regarding further development of multi gene panel testing, more research is required to establish both the optimal care of patients with cancer (specific treatments like PARP inhibitors) and the management of unaffected individuals (chemoprevention and/or prophylactic surgeries). Early detection in these patients as well as prophylactic measures will significantly increase the chance of survival. Therefore, multi gene panel testing is not yet ready to be used outside clear guidelines. In conclusion, studies on additional cohorts will be needed to better define the real prevalence, penetrance and the variants of these genes, as well as to describe clear evidence-based guidelines for these patients.

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