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BRCA deletion/duplication analysis

Cancer
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Report in 840Hrs

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Genetic test for BRCA1/2 structural changes.

₹35,816₹51,166

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BRCA Deletion/Duplication Analysis - Comprehensive Medical Test Guide

  • Section 1: Why is it done?
    • Test Purpose: This test detects large deletions and duplications in the BRCA1 and BRCA2 genes using molecular techniques such as multiplex ligation-dependent probe amplification (MLPA), comparative genomic hybridization (CGH), or next-generation sequencing (NGS). These structural variants represent approximately 5-10% of pathogenic BRCA mutations and are often missed by standard sequencing methods.
    • Primary Indications: Individuals with a family history of hereditary breast and ovarian cancer syndrome (HBOC), strong personal history of breast cancer (especially early-onset or triple-negative), ovarian cancer, pancreatic cancer, prostate cancer, or male breast cancer; ethnicity associated with founder mutations (Ashkenazi Jewish ancestry); prior negative BRCA sequencing result with high clinical suspicion for BRCA mutation.
    • Clinical Timing: Performed as part of comprehensive BRCA testing, often after initial BRCA1/BRCA2 sequencing returns negative or inconclusive results. May be ordered simultaneously with sequencing or as reflexive testing. Particularly important in families where clinical suspicion remains high despite negative sequencing results.
    • Screening Context: Part of comprehensive hereditary cancer risk assessment; assists in cancer risk stratification; informs personalized surveillance and prevention strategies; guides family member testing and counseling.
  • Section 2: Normal Range
    • Normal Result (Negative): No deletions or duplications detected in the BRCA1 or BRCA2 genes. Two intact copies of each exon present (diploid state = 2 copies per exon). All probe signals are within expected range indicating normal gene copy numbers.
    • Reference Values: Copy number = 2.0 (or ratio = 1.0) for each exon analyzed. Results are typically reported as a ratio or log2 ratio of test sample to reference sample. Normal range for log2 ratio approximately -0.3 to +0.3. Normal range for copy number ratio approximately 0.8 to 1.2.
    • Abnormal Result (Positive): Deletion: Copy number = 1.0 (monosomic); log2 ratio approximately -1.0; loss of one copy of one or more exons. Duplication: Copy number = 3.0 (trisomic); log2 ratio approximately +0.5 to +1.0; gain of one extra copy of one or more exons. Larger deletions/duplications show more pronounced ratio changes.
    • Interpretation Criteria: Pathogenic: Large exonic deletions/duplications causing frameshift or loss of function; single or multiple exons missing/duplicated. Likely Pathogenic: Deletions/duplications affecting critical domains or multiple exons with high likelihood of pathogenicity. Variant of Uncertain Significance (VUS): Small duplications affecting non-critical regions; single exon duplications. Benign: Copy number variations present in general population; duplications not affecting protein function.
  • Section 3: Interpretation
    • Deletion Results: Single exon deletion: Loss of genetic material likely disrupting normal gene function; typically pathogenic. Multiple contiguous exon deletion: Large structural variant causing loss of significant protein coding sequence; highly pathogenic. Whole gene deletion: Complete loss of BRCA1 or BRCA2 gene; severely pathogenic with highest cancer risk. Results in haploinsufficiency or truncated protein production.
    • Duplication Results: Single exon duplication: Pathogenicity depends on location and reading frame. May cause frameshift mutation (pathogenic) or in-frame duplication (potentially benign). Multiple exon duplication: More likely pathogenic due to dosage imbalance. In-frame tandem duplications may be tolerated better than frame-shifting duplications.
    • Zygosity Interpretation: Heterozygous deletion/duplication (1 copy change): Individual carries one mutant and one normal allele; moderate to high cancer risk; autosomal dominant inheritance pattern; carrier can pass mutation to 50% of offspring. Homozygous deletion (0 copies): Extremely rare; severe phenotype; usually embryonic lethal in homozygous state.
    • Clinical Significance: Positive deletion in BRCA1: Lifetime breast cancer risk 45-87%; ovarian cancer risk 40-46%; increased risks for pancreatic and prostate cancers. Positive deletion in BRCA2: Lifetime breast cancer risk 40-84%; ovarian cancer risk 10-27%; male breast cancer risk increased; pancreatic cancer risk elevated. Deletions typically associated with higher penetrance than point mutations.
    • Factors Affecting Results: Technical sensitivity and specificity of method used (MLPA approximately 99%, array CGH approximately 98%). Mosaicism (present in <20% of cells may be missed). Quality of DNA sample. Presence of pseudogenes or highly homologous regions affecting accuracy. Complex rearrangements may require additional confirmation with different methodology.
    • Intermediate Cases (VUS): Some duplications, especially small in-frame duplications, may be classified as VUS requiring parental testing, functional studies, or population frequency analysis. Repeat testing with alternative method recommended for confirmation. Genetic counseling essential for VUS results. Reclassification may occur as databases accumulate evidence.
  • Section 4: Associated Organs
    • Primary Organ Systems: Mammary glands (breast tissue); ovarian tissue; reproductive system (including fallopian tubes); pancreatic tissue; prostate gland; male accessory glands. BRCA proteins function in DNA repair throughout the body, affecting all tissue types but with particular cancer predisposition in these organ systems.
    • Associated Medical Conditions - BRCA1 Deletion: Hereditary Breast and Ovarian Cancer Syndrome (HBOCS); early-onset breast cancer (often <50 years); ovarian cancer; fallopian tube cancer; primary peritoneal cancer; pancreatic cancer; prostate cancer (especially aggressive forms); male breast cancer; associated with triple-negative breast cancer phenotype.
    • Associated Medical Conditions - BRCA2 Deletion: Hereditary Breast and Ovarian Cancer Syndrome; male breast cancer (higher risk than BRCA1); bilateral breast cancer; ovarian cancer; pancreatic cancer; prostate cancer; bladder cancer; stomach cancer; melanoma; small proportions may have Fanconi anemia features in biallelic carriers.
    • Complications of Positive Results: Metastatic cancer development if not detected early; complications from prophylactic surgeries (bilateral mastectomy, oophorectomy); surgical menopause effects; increased anxiety and psychological burden; recurrent surveillance-related stress; treatment toxicity from chemotherapy or radiation; secondary malignancies from cancer treatment.
    • Tissue-Specific Manifestations: Breast: Most common cancer site; earlier onset age; higher grade tumors. Ovary: Often presents with advanced stage disease. Pancreas: Highly aggressive; poor prognosis; presents at advanced stage. Prostate: Variable age of onset; some cases aggressive. Male breast: Rare but highly penetrant in BRCA2 carriers.
  • Section 5: Follow-up Tests
    • Confirmatory Testing: If deletion/duplication detected, recommend confirmatory testing with alternative methodology (e.g., if initial test was MLPA, confirm with array CGH or NGS). Sequencing of breakpoints to define exact boundaries of deletion/duplication. Southern blot analysis for large deletions if needed. Functional studies for VUS duplications to assess impact on protein.
    • Family Testing: Testing of at-risk blood relatives (parents, siblings, children) to determine who carries mutation. Parental testing particularly important for VUS to assess segregation. Allows risk stratification of extended family members. Testing recommendations for first-degree relatives: siblings (25-50% risk depending on parental status); adult children (50% if proband is heterozygous); parents.
    • Imaging Surveillance: Baseline mammography (if not already done); supplemental screening MRI of breast (annual or semi-annual); pelvic ultrasound (to screen ovaries); consideration of CT imaging for pancreatic screening in high-risk families. Frequency typically annual starting at age 25-30 depending on family cancer history and specific mutation.
    • Tumor Molecular Testing: If cancer develops, perform BRCA deletion/duplication analysis on tumor tissue to confirm somatic second hit mutation. HRD (homologous recombination deficiency) testing using tumor tissue. PARP inhibitor eligibility assessment. Immunohistochemistry for BRCA1/BRCA2 expression.
    • Related Genetic Tests: Panel testing of other hereditary cancer genes (TP53, PTEN, CHEK2, PALB2, MLH1, MSH2, MSH6, PMS2, EPCAM). Homologous recombination repair gene testing. Mismatch repair gene testing. Lynch syndrome testing if colorectal cancer present.
    • Monitoring Recommendations: Clinical breast exams every 6 months starting age 25. Mammography annually starting age 40 (or age 30 for higher-risk families). Breast MRI annually starting age 25-30. Pelvic imaging (ultrasound +/- CA-125) annually starting age 30-35. Pancreatic surveillance (EUS or MRI/MRCP) annually starting age 40-50 in affected families. Prostate surveillance (PSA testing) annually in male carriers starting age 45.
  • Section 6: Fasting Required?
    • Fasting Requirement: NO fasting required. This is a genetic test requiring blood or saliva sample. Fasting does not affect DNA analysis. Test can be performed at any time of day.
    • Sample Collection: Peripheral blood draw: 5-10 mL of whole blood in EDTA (lavender-top) tube. OR Saliva sample: 2-10 mL of saliva in provided collection tube (if available). OR Buccal swab: Oral mucosal cells collected via swab. Sample should be labeled with patient identifying information and date of collection.
    • Special Preparation: No special dietary restrictions. No medication restrictions. No fasting period needed. Patient may eat and drink normally before test. Can take all regular medications as scheduled. Timing of sample collection not dependent on meal times. Sample stability maintained for several weeks when properly stored.
    • Pre-test Requirements: Pre-test genetic counseling strongly recommended. Review of family history and personal cancer history. Informed consent for genetic testing and possible incidental findings. Discussion of privacy implications and genetic discrimination protections. Insurance considerations and testing coverage verified prior to sample collection.
    • Post-Test Requirements: Post-test genetic counseling mandatory for all results, especially positive findings. Results discussion with healthcare provider. If positive: surveillance plan establishment, medication/prevention options counseling, family notification discussion. No activity restrictions after blood draw; possible bruising at draw site. Resume normal activities immediately.
    • Turnaround Time: Typically 2-4 weeks depending on laboratory. CLIA-certified laboratories required for all testing. Complex cases requiring additional studies may extend turnaround time. Expedited testing (1-2 weeks) may be available for newly diagnosed cancer patients for an additional fee. Results provided to ordering provider or directly to patient through secure portal.

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