Common Hereditary Cancer Screening Panel

Hereditary cancer syndromes have been observed in approximately 5-10% of diagnosed cancers. Hereditary cancers tend to occur at an earlier age (<50 years), and tumors often occur bilaterally or are multifocal. Multiple family members are often affected. Hereditary cancers may include a less frequently affected gender (breast cancer in males), can be associated with other clinical features, and occur with a higher predisposition in specific ethnicities, such as the Ashkenazi Jewish population (Lindor et al. 2008. PubMed ID: 18559331).

Testing asymptomatic and symptomatic individuals at increased risk of a hereditary cancer syndrome may inform genetic counseling, screening, prevention strategies, and treatment (Weitzel et al. 2011. PubMed ID: 21858794; ACOG. 2019. PubMed ID: 31764758). Multigene panel testing may be considered if an individual’s personal or family history may be explained by one or more types of hereditary cancer syndromes (Robson et al. 2015. PubMed ID: 26324357). It also may be considered if a positive finding will impact medical management for the individual or their at-risk family members.

This 55-gene panel identifies hereditary risk associated with at least 11 common types of cancer: breast, ovarian, uterine, prostate, colorectal, pancreatic, gastric, renal, lung, endocrine, and skin. Additional types of cancer, polyposis predisposition, and cancer-related syndromes are also included. Of note, several genes on this panel are associated with rare autosomal recessive cancer-related syndromes that may pose a risk to offspring if an individual’s partner is also a carrier.

The panel includes clinically actionable genes with medical society guidelines available on risk management for carriers of pathogenic germline variants, as well as genes with emerging cancer associations (Miller et al. 2023. PubMed ID: 37347242; Pluchino and D'Amico. 2020. PubMed ID: 32298647).

Hereditary cancers associated with genes on this panel typically have an early age of onset and display autosomal dominant inheritance. However, autosomal recessive inheritance is also reported (MUTYH and NTHL1, for example). Most pathogenic variants 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.

Clinical sensitivity for this panel is highly dependent on the type of cancer, patient, age, and personal and family history. A study of 165,000 individuals that underwent multigene germline panel testing for hereditary cancer predisposition reported pathogenic variants in 8.1% to 13.8% of tested individuals depending on cancer type (LaDuca et al. 2020. PubMed ID: 31406321).

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

This panel typically provides approximately 97.97% 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.

Of note, Next Generation Sequencing analysis of the SDHA gene is technically challenging due to the presence of segmental duplications and paralogy. Therefore, analysis of CNVs in this region is not included in this test.

DNA analysis of the PMS2 gene is complicated due to the presence of several pseudogenes. One particular pseudogene, PMS2CL, has high sequence similarity to PMS2 exons 11 to 15 (Blount et al. 2018. PubMed ID: 29286535). Next-generation sequencing (NGS) based copy number variant (CNV) analysis can detect deletions and duplications involving exons 1 to 10 of PMS2 but has less sensitivity for exons 11 through 15. Multiplex ligation-dependent probe amplification (MLPA) can detect deletions and duplications involving PMS2 exons 1 to 15. Of note, PMS2 MLPA is not typically included in this test but can be ordered separately using test code 6062, if desired