BRCANext™

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BRCANext™ is a management guidelines-based panel that includes 18 genes associated with hereditary breast and/or gynecologic cancers. 

Why Is This Important?

• Option to modify the frequency and initial age of surveillance for various cancers (e.g. mammogram and breast MRI)
• Consideration of prophylactic oophorectomy or mastectomy, or other risk-reducing measures as appropriate
• Option to tailor treatments (e.g. PARP inhibitors for BRCA1/BRCA2)
• Identify at-risk family members

When To Consider Testing?

• Cancer histories that are suspicious for both hereditary breast-ovarian cancer and Lynch syndrome
• Ashkenazi Jewish ancestry
• Multiple close family members with ovarian or uterine and other cancers (on the same side of the family)
• Multiple primary cancers in one person (e.g. uterine and breast or thyroid cancer)
• Abnormal MSI/IHC 
• Breast cancer diagnosed before 45 years old, triple-negative breast cancer before 60 years, or uterine cancer diagnosed before 50 years
• Ovarian, pancreatic, male breast, or metastatic prostate cancer at any age

Test Method

BRCANext™ analyses 18 genes. These genes (excluding EPCAM) are evaluated by next-generation sequencing (NGS) or Sanger sequencing of all coding domains and well into the flanking 5’ and 3’ ends of all the introns and untranslated regions. The inversion of coding exons 1-7 of the MSH2 gene and the BRCA2 Portuguese founder mutation, c.156_157insAlu (also known as 384insAlu) are detected by NGS and confirmed by MLPA. Clinically significant intronic findings beyond 5 base pairs are always reported. Intronic variants of unknown or unlikely clinical significance are not reported beyond 5 base pairs from the splice junction.

Additional Sanger sequencing is performed for any regions missing or with insufficient read depth coverage for reliable heterozygous variant detection. Potentially homozygous variants, variants in regions complicated by pseudogene interference, and variant calls not satisfying depth of coverage and variant allele frequency quality thresholds are verified by Sanger sequencing. Gross deletion/duplication analysis is performed for the covered exons and untranslated regions of all sequenced genes using read-depth from NGS data with confirmatory multiplex ligation-dependent probe amplification (MLPA) and/or targeted chromosomal microarray. For EPCAM, only gross deletions encompassing the 3’ end of the gene are reported. Gross deletion/duplication analysis of PMS2 is performed using MLPA. If a deletion is detected in exons 13, 14, or 15 of PMS2, double-stranded sequencing of the appropriate exon(s) of the pseudogene, PMS2CL, will be performed to determine if the deletion is located in the PMS2 gene or pseudogene. 

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