Are your BRCA1/2 tests sufficient?

Breast cancer susceptibility genes 1 and 2 (BRCA1 and BRCA2) encode proteins functioning as tumor suppressors to maintain genomic stability. Mutations in BRCA1/2 genes can cause DNA damage, significantly increasing the risk of developing various types of cancers, especially cancers of the breast, ovary, prostate, and pancreas. Pathogenic mutations in BRCA1 and BRCA2 are associated with a 7.6- or 5.2-fold increase of breast cancer risk, respectively.1 While the lifetime risk of breast and ovarian cancers are 12% and 1.3% in the general population, the cumulative lifetime risk is 72 % and 44 % in BRCA1 mutation carriers and 69 % and 17 % in BRCA2 mutation carriers, respectively.2

Clinical studies have demonstrated that mutations in the BRCA1/2 genes are associated with the sensitivity of multiple cancers to poly ADP-ribose polymerase (PARP) inhibitors.3-6 The U.S. Food and Drug Administration (FDA) has approved four PARP inhibitors as monotherapy or maintenance therapy for breast, ovarian, prostate, or pancreatic cancer patients with BRCA1/2 mutations: olaparib, rucaparib, niraparib, and talazoparib.7 Therefore, accurate detection of BRCA1/2 mutations has an immense impact on clinical management of disease including eligibility for PARP inhibitor therapy.

BRCA1/2 mutations can be single nucleotide variations (SNVs), small insertions/deletions (INDELs), or large genomic rearrangements (LGRs), which are defined as deletions or insertions involving a significant portion of one or more exon(s). LGRs account for up to 27% of the BRCA1 and 5% of BRCA2 disease-causing mutations, with a strong founder effect accounting for about 1/3 of all cancer diagnosis in some populations.8

SNV and small INDEL mutations in BRCA1/2 can be detected using methods based on next-generation sequencing (NGS) or polymerase chain reaction (PCR). However, PCR is limited by low-plexity and its ability to detect only known BRCA1/2 mutations. While being capable of high throughput for all possible mutations in BRCA1/2, the most widely used short-read NGS panel methodology generally can’t detect LGRs without additional modifications to the sequencing pipeline. Consequently, BRCA1/2 LGRs are frequently missed in molecular screening with PCR-based methods or NGS panels, the two most widely-employed techniques in the current diagnostics market. Subsequently, the detection of BRCA1/2 LGRs mainly relies on alternative NGS-independent assays, such as multiplex ligation-dependent probe amplification (MLPA), microarrays, or whole genome/exon sequencing, leading to increased cost and longer turnaround times.9

Ideally, one BRCA1/2 test should detect all mutations at once to help guide evidence-based clinical decisions in cancer patient management. Among all available methods, NGS panels can be the choice test when incorporating certain adjustments in the bioinformatics pipeline and/or panel design to enable copy number detection. After pipeline adjustments are made, a validation process is required to prove the effectiveness of detecting LGRs in addition to SNVs and small INDELs. Due to the scarcity of clinical samples containing LGRs, well-characterized and patient-like reference materials are ideal surrogates for hard-to-source clinical samples for assessing sensitivity and specificity of the pipeline as recommended by the diagnostic community.10

LGC Clinical Diagnostics has developed a unique set of BRCA1/2 LGR reference materials to support the industry’s need to develop and validate BRCA1/2 LGR NGS panels. The Seraseq® BRCA1/2 LGR reference material and mutation mixes are provided in two formats:

These BRCA1/2 reference materials all include 10 variants in each BRCA1 and BRCA2 genes, ranging in size from SNVs to INDELs over 500 bp, and covering a variety of variant types to provide adequate challenges for the validation process. See our product sheet by clicking here, or on the button below:

Features and Benefits

  • Develop, monitor, validate and challenge your hybrid capture-based targeted NGS assays with confidence using a highly multiplexed reference material containing biomarkers important in BRCA-driven cancers.
  • Single sample with 20 pathogenic BRCA1/2 variants (11 LGRs, 9 deletions, 5 SNVs, 4 indels, and 2 insertions).
  • Mutation targets quantitated by highly sensitive dPCR assays, and orthogonally analyzed by NGS.
  • All mutations are blended against the well-characterized GM24385 human genomic DNA as ‘wildtype’ background material.
  • Available as full process (FFPE curl) or purified genomic DNA at various allele frequencies suited for either somatic or germline testing.
  • Manufactured in GMP-compliant and ISO 13485-certified facilities.

Please visit our website to find more information on our Seraseq BRCA1/2 LGR reference materials and learn how these products can help with your BRCA1/2 LGR assay development and validation:


Call 800.676.1881 or email


1. Hu C, et al. A Population-Based Study of Genes Previously Implicated in Breast Cancer. N Engl J Med. 2021;384(5): 440–451.

2. Nitschke AS, et al. Long-Term Non-Cancer Risks in People with BRCA Mutations following Risk-Reducing Bilateral Salpingo-Oophorectomy and the Role of Hormone Replacement Therapy: A Review. Cancers (Basel). 2023;15(3): 711.

3. Mirza, MR, et al. Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer. N. Engl. J. Med. 2016;375:2154–2164.

4. Robson, M, et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. N. Engl. J. Med. 2017;377:523–533.

5. Swisher EM, etc. Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 Part 1): an international, multicentre, open-label, phase 2 trial. Lancet Oncol. 2017;18(1):75-87.

6. Litton JK, etc. Talazoparib in Patients with Advanced Breast Cancer and a Germline BRCA Mutation. N Engl J Med. 2018 Aug 23;379(8):753-763.

7. Ragupathi A, et al. Targeting the BRCA1/ 2 deficient cancer with PARP inhibitors: Clinical outcomes and mechanistic insights. Front Cell Dev Biol. 2023;11:1133472.

8. Wallace AJ. New challenges for BRCA testing: a view from the diagnostic laboratory. Eur J Hum Genet. 2016 Sep;24 Suppl 1:S10-8.

9. Concolino P & Capoluongo E. Detection of BRCA1/2 large genomic rearrangements in breast and ovarian cancer patients: an overview of the current methods. In: Expert Rev Mol Diagn. 2019;19(9):795-802.

10. Jennings LJ, et al. Guidelines for Validation of Next-Generation Sequencing-Based Oncology Panels: A Joint Consensus Recommendation of the Association for Molecular Pathology and College of American Pathologists. J Mol Diagn. 2017;19(3):341-365.

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