Cancer Panel

Hereditary cancer syndromes have been observed in approximately 5-10% of diagnosed cancers (Mauer et al. 2013. PubMed ID: 24113346). 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).

The results of testing for a group of hereditary cancers can be important for counseling, screening and treatment (O’Daniel and Lee. 2012. PubMed ID: 22846728; Imyanitov and Byrski. 2013. PubMed ID: 23548133). Additionally, assessment of multiple genes associated with hereditary cancers can be useful in determining personal or familial risks (Foulkes. 2008. PubMed ID: 19005198).

Genes involved in multiple hereditary cancer syndromes are mostly inherited in an autosomal dominant manner. As several types of cancers may be found in one pedigree, this test may help in the differential diagnosis and rule out particular syndromes by simultaneously analyzing multiple genes involved in hereditary cancers.

Phenotype clusters from this panel include: breast cancer, colorectal cancer, endocrine cancer, endometrial cancer, gastric cancer, melanoma predisposition, neurological tumors, ovarian cancer, pancreatic cancer, paraganglioma and pheochromocytoma, pediatric cancer, polyposis, prostate cancer, renal cancer, sarcoma, and thyroid cancer.

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

Genes tested in this panel have been implicated in hereditary cancer, and although individually these genes may be involved in a minority of cancers, the combination of highly, moderately, and mildly penetrant pathogenic variants may be responsible for a significant portion of hereditary cancers.

Clinical sensitivity for this panel is highly dependent on the type of cancer, specific ethnicity, and age of patients.

One study of 227 individuals with a personal or family history of cancer undergoing multigene panel testing found that 12% of individuals had a pathogenic variant and 29.5% had a variant of uncertain significance (Hermel et al. 2017. PubMed ID: 27401692). Changes in medical care due to panel testing results occurred in approximately 13% of cases.

Another study of 10,000 patients with various cancers referred for multigene panel testing found a molecular diagnosis in 9% of patients tested (Susswein et al. 2016. PubMed ID: 26681312). Positive rates were found in 9.7%, 13.4%, and 14.8% for patients with breast, ovarian, or colon/stomach cancer, respectively.

Clinical sensitivity of commonly tested genes is given based on each disorder:

CHEK2-related Cancers: Pathogenic CHEK2 sequence variants are reported in hereditary breast cancer and have been reported in 4.5% of cases (Castéra et al. 2014. PubMed ID: 24549055).

Familial Adenomatous Polyposis (FAP): Pathogenic APC sequence variants are found in >90% of individuals with FAP (Laken et al. 1999. PubMed ID: 10051640). Gross deletions/duplications have been reported in up to 12% of APC patients (Jasperson et al. 2017. PubMed ID: 20301519).

Hereditary Breast and Ovarian Cancer (HBOC): The overall prevalence of germline BRCA1 or BRCA2 pathogenic variants in the general population is 1:400 to 1:800, with higher rates depending on the specific ethnicity, such as 1:40 in the Ashkenazi Jewish population. Nucleotide substitutions and small insertions or deletions are found in about 90% of individuals with an identifiable pathogenic variant. For individuals with pathogenic variants in these genes, BRCA1 variants were observed in 63% and BRCA2 variants in 37% (Petrucelli et al. 2016. PubMed ID: 20301425). Copy number variants (CNVs) are found in approximately 10% of individuals with an identifiable BRCA1/2 germline pathogenic variant, with 90% of these in BRCA1 and 10% in BRCA2 (Petrucelli et al. 2016. PubMed ID: 20301425).

A study by Walsh et al (2011) found approximately 6% of patients with hereditary ovarian cancers who do not have pathogenic variants in BRCA1 or BRCA2 have pathogenic variants in genes such as BARD1, BRIP1, CHEK2, MRE11, NBN, PALB2, RAD50, RAD51C, and TP53 (Walsh et al. 2011. PubMed ID: 22006311). Another study by Castéra et al. found that around a third of the deleterious variants identified in their patient cohort were in genes outside of BRCA1/2, including CDH1, CHEK2, PALB2, and TP53 (Castéra et al. 2014. PubMed ID: 24549055). HBOC-associated gross deletions have been reported for the RAD51C (Vuorela et al. 2011. PubMed ID: 21750962), PALB2 (Antoniou et al. 2014. PubMed ID: 25099575), and TP53 (Melhem-Bertrandt et al. 2012. PubMed ID: 21761402) genes.

Hereditary Diffuse Gastric Cancer (HDGC): The clinical sensitivity of pathogenic CDH1 sequence variants is 30% for HDGC families (Carneiro et al. 2007. PubMed ID: 17513507). Large deletions have been detected in the CDH1 gene in up to 4% of patients (Kaurah and Huntsman. 2014. PubMed ID: 20301318).

Hereditary Paraganglioma-Pheochromocytoma Syndrome: Although the majority of hereditary paraganglioma-pheochromocytoma (PGL/PCC) syndrome tumors are sporadic (non-familial), approximately 13% of all PGL/PCC tumors are caused by germline pathogenic variants in known PGL/PCC syndrome genes (Welander et al. 2011. PubMed ID: 22041710).

Juvenile Polyposis Syndrome (JPS): This test is predicted to identify a pathogenic BMPR1A sequence variant in 11-22% and a pathogenic SMAD4 sequence variant in 20-26% of patients diagnosed with JPS. Deletion/duplication analysis is predicted to identify a BMPR1A pathogenic variant in 1-2% and a SMAD4 pathogenic variant in 2-9% of patients diagnosed with JPS (Larsen Haidle and Howe. 2017. PubMed ID: 20301642).

Li-Fraumeni Syndrome: Sequencing the TP53 gene can detect approximately 95% of patients with Li-Fraumeni syndrome. Deletions in the TP53 gene have been detected in 1% of Li-Fraumeni cases (Schneider et al. 2013. PubMed ID: 20301488).

Lynch Syndrome: Depending on the clinical criteria used to make a diagnosis (Amsterdam or “Revised Bethesda”), 30-50% and 15-20% of Lynch patients have a detectable pathogenic MLH1 and MSH2 sequence variant, respectively (Syngal et al. 2000. PubMed ID: 10978352). A pathogenic sequence variant in MSH6 is detected in <2% of patients that meet the stringent Amsterdam I criteria but is detected in ~12% of atypical Lynch/HNPCC families (Peltomäki and Vasen. 2004. PubMed ID: 15528792). A pathogenic PMS2 sequence variant is detected in 1-2% of Lynch patients (Peltomäki and Vasen. 2004. PubMed ID: 15528792) and ~50% of constitutional mismatch repair-deficiency patients (Wimmer and Etzler. 2008. PubMed ID: 18709565). The clinical sensitivity of EPCAM sequence variants in Lynch syndrome is unknown as no pathogenic sequence variants have been reported for this disease; however, sequence variants in the EPCAM gene are known to be causative for congenital tufting enteropathy. The clinical sensitivity of EPCAM deletions is 1-3% of individuals with Lynch syndrome (Idos and Valle. 2021. PubMed ID: 20301390). Lynch syndrome is attributed to deletions in the MLH1, MSH2, MSH6, and PMS2 genes in approximately 5%, 20%, 7%, and 20% of cases, respectively (Idos and Valle. 2021. PubMed ID: 20301390).

Melanoma: 25-50% of familial melanoma cases have causative germline variants in CDKN2A, and there is a 1-3% chance that an individual with primary melanoma has a causative germline variant in CDKN2A (Nelson and Tsao. 2009. PubMed ID: 19095153; Ibrahim et al. 2009. PubMed ID: 19400696). Only 2% of the families in the Geno-MEL study carried CDK4 pathogenic variants (Goldstein et al. 2006. PubMed ID: 17047042). Clinical sensitivity for CDKN2A and CDK4 deletions/duplications is not currently known.

Multiple Endocrine Neoplasia type 2 and Familial Medullary Thyroid Carcinoma: This test is predicted to detect pathogenic variants in >95% of cases (Marquard and Eng. 2015. PubMed ID: 20301434).

MUTYH-Associated Polyposis: By definition, nearly all (~99%) MAP patients have biallelic germline pathogenic variants in MUTYH. However, pathogenic variants in MUTYH are also found in ~25% of patients initially diagnosed with familial adenomatous polyposis (FAP; Sampson et al. 2003. PubMed ID: 12853198). Clinical sensitivity for MUTYH deletions/duplications is not currently known.

Pancreatic Cancer: Pathogenic ATM heterozygous variants in familial pancreatic cancer can be observed in up to 5% individuals (Bartsch et al. 2012. PubMed ID: 22664588; Solomon et al. 2012. PubMed ID: 23187834). Pathogenic variants in BRCA1, BRCA2, and CDKN2A have recently been reported in 1.2%, 3.7%, and 2.5% of individuals, respectively, in a study of familial pancreatic cancer (Zhen et al. 2015. PubMed ID: 25356972). One large study showed that 21% of individuals or families with Lynch syndrome had at least one case of pancreatic cancer (Kastrinos et al. 2009. PubMed ID: 19861671).

Peutz-Jeghers Syndrome: Approximately 55% of patients with a positive family history and 70% of patients with no family history of Peutz-Jeghers syndrome will be detected by STK11 sequencing. Approximately 45% of patients with a positive family history or 21% of patients with no family history of Peutz-Jeghers syndrome will have a pathogenic variant in STK11 by deletion analysis (McGarrity et al. 2016. PubMed ID: 20301443).

POLD1 and POLE Colorectal Cancer Predisposition: Pathogenic sequence variants in the POLD1 and POLE genes have been observed in 0.2% and 0.3-0.6% of individuals with colorectal cancer, respectively (Chubb et al. 2015. PubMed ID: 25559809).

Prostate Cancer: In a recent study of 692 men with documented metastatic prostate cancer, pathogenic variants in these genes were identified, including ATM (11 pathogenic variants [13% of total]), BRCA1 (6 [7%]), BRCA2 (37 [44%]), CHEK2 (10 [12%]), and PALB2 (3 [4%]; Pritchard et al. 2016. PubMed ID: 27433846).

PTEN Hamartoma Syndrome: This test is predicted to detect causative PTEN pathogenic variants in ~80% of patients with Cowden syndrome (CS), ~65% of patients with Bannayan-Riley-Ruvalcaba syndrome (BRRS) and ~20% of patients with Proteus syndrome (PS). Large deletions are predicted to be detected in ~11% of patients with BRRS, but the sensitivity is not known for other PTEN related disorders (Eng 2003. PubMed ID: 12938083).

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel typically provides 99.9% 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. We define coverage as ≥20X NGS reads or Sanger sequencing.

The PHOX2B exon 3 polyalanine region is not covered.

This panel also includes testing for the inversion of exons 1-7 in MSH2.

Deletion and duplication testing for STK11, NF1, and PMS2 is performed using NGS, but CNVs detected in these genes are confirmed via multiplex ligation-dependent probe amplification (MLPA).

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. 

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.