Breast Cancer - Expanded Risk Panel

This panel analyzes 21 breast cancer susceptibility genes. BRCA1, BRCA2, CDH1, PALB2, PTEN, TP53, and STK11 are considered high-risk genes. ATM, BARD1, BMPR1A, CHEK2, NF1, RAD51C, and RAD51D are considered moderate-risk genes. Pathogenic germline variants in high-risk genes may confer up to or greater than a 60% lifetime risk of breast cancer (Mavaddat et al. 2013. PubMed ID: 23628597; Mai et al. 2016. PubMed ID: 27496084; Xicola et al. 2019. PubMed ID: 31296550; Wendt and Margolin. 2019. PubMed ID: 30606073). Pathogenic germline variants in moderate-risk genes may confer approximately 15% to 40% lifetime risk of breast cancer (Marabelli et al. 2016. PubMed ID: 27112364; Uusitalo et al. 2016. PubMed ID: 26926675; Hu et al. 2020. PubMed ID: 32091585; Dorling et al. 2021. PubMed ID: 33471991). Medical society guidelines are available for high- and moderate-penetrance genes included on this panel (Wendt and Margolin. 2019. PubMed ID: 30606073; Pluchino and D'Amico. 2020. PubMed ID: 32298647).

This panel also assesses several emerging genes that may confer an increased lifetime risk of breast cancer compared to the 12.9% lifetime risk observed in the general population (National Cancer Institute, SEER Program). However, for many of these genes absolute risk of breast cancer has not been defined. These genes include BRIP1, FANCC, FANCM, MRE11, RAD50, RECQL, and XRCC2.

Most of the genes on this panel are associated with early-onset breast cancer (≤45 years of age), bilateral or multiple primary breast cancers, early-onset ovarian cancer (including fallopian tube and primary peritoneal cancers), male breast cancer, or a family history of breast or other early onset cancers. Variants in some genes are also more frequent in individuals of Ashkenazi Jewish ancestry (Pruthi et al. 2010. PubMed ID: 21123638; Petrucelli et al. 2022. PubMed ID: 20301425). Genetic testing of highly, moderately, and mildly penetrant genes may inform genetic counseling, screening, prevention strategies, and treatment, as well as identify at-risk family members (Manahan et al. 2019. PubMed ID: 31342359; Pluchino and D'Amico. 2020. PubMed ID: 32298647).

The genes included on this panel may be associated with susceptibility to other cancers as well as rare cancer syndromes that may include increased risk of breast cancer. Several genes on this panel are also associated rare autosomal recessive conditions that may pose a risk to offspring if an individual’s partner is also a carrier.

Hereditary cancers associated with genes on this panel typically have an early age of onset and display autosomal dominant inheritance, although penetrance is incomplete. Several of the genes on this panel are also associated with rare autosomal recessive cancer syndromes. Most pathogenic variants in these genes are inherited from one or both parents. In some instances, pathogenic variants may arise de novo (PTEN and TP53, for example).

The genes on this panel are involved in DNA repair, cell cycle checkpoint regulation, maintenance of genomic stability, and other biological functions (Lee and Muller. 2010. PubMed ID: 20719876).

See individual gene summaries for information about the molecular biology of gene products and spectra of pathogenic variants.

The prevalence of germline BRCA1 or BRCA2 pathogenic variants in the general population is 1:400 to 1:500 (Petrucelli et al. 2022. PubMed ID: 20301425). Certain ancestral populations have significantly elevated prevalence rates for BRCA1 and BRCA2, such as the Ashkenazi Jewish population (1:40) and the Inuit population from Ammassalik, Greenland (1:10 to 1:100) (Petrucelli et al. 2022. PubMed ID: 20301425). Pathogenic variants in genes other than BRCA1 and BRCA2 are often tested selectively. Although individually these genes may be involved in a minority of inherited breast cancer genes, the combination of high- and moderate-risk genes may be responsible for a significant portion of hereditary breast cancer (Turnbull and Rahman. 2008. PubMed ID: 18544032).

This test is performed using Next Generation Sequencing (NGS) with additional Sanger sequencing as necessary.

This panel typically provides approximately 99.7% coverage of all coding exons of the genes plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. Coverage is defined as ≥20X NGS reads or Sanger sequencing.