Test Catalog

Test ID: BRCRC    
Hereditary Breast and Colorectal Cancer Panel, Next-Generation Sequencing, Varies

Useful For Suggests clinical disorders or settings where the test may be helpful

Establishing a hereditary susceptibility to cancer


Evaluation of families with a history suggestive of a predisposition to both breast and colorectal cancer


Identification of familial BRCA1, BRCA2, TP53, PTEN, CDH1, STK11, MLH1, MSH2, MSH6, PMS2, or EPCAM variants to allow for predictive testing in family members

Genetics Test Information Provides information that may help with selection of the correct genetic test or proper submission of the test request

This test includes next-generation sequencing, Sanger sequencing, array comparative genomic hybridization, and multiplex ligation-dependent probe amplification to evaluate for variants and large deletions/duplications in the BRCA1, BRCA2, TP53, PTEN (including the promoter), CDH1, STK11, MLH1, MSH2, MSH6, PMS2, and EPCAM genes. Sanger sequencing may also be performed to confirm detected variants.


Prior Authorization is available for this assay; see Special Instructions.

Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test

While the risk for breast and colorectal cancer in the general population is 12% and 6%, respectively, these cancers are rarely attributable to a single abnormal gene that predisposes individuals to increased risks for cancer in a family. Given the prevalence of breast and colon cancer in the general population, it can be challenging to evaluate families with both breast and colon cancer for a possible hereditary predisposition. This panel allows for evaluation of the most common genes associated with both hereditary breast and hereditary colon cancer. Additionally, there is recent evidence to suggest an increased risk for breast cancer associated with the genes that cause Lynch syndrome. Therefore, evaluation for the genes on this panel may be useful for families suspicious of either a hereditary predisposition to breast cancer, colorectal cancer or both.


Hereditary Breast and Ovarian Cancer

Hereditary breast and ovarian cancer (HBOC) is an autosomal dominant hereditary cancer syndrome associated with germline variants in the BRCA1 or BRCA2 genes. Variants within these 2 genes account for the majority of hereditary breast and ovarian cancer families. HBOC is predominantly characterized by young-onset breast cancer and ovarian cancer. However, HBOC is also associated with increased risks for prostate cancer, pancreatic cancer, fallopian tube cancer, and male breast cancer. HBOC is highly penetrant; the risk for developing an invasive breast cancer is about 60% to 65% and the risk for developing ovarian cancer is about 40% by age 70. Some individuals develop multiple primary or bilateral cancers.


Hereditary Breast Cancer

While pathogenic BRCA1 and BRCA2 variants account for the majority of hereditary breast cancer, alterations in other genes may be present in families in which a BRCA1 or BRCA2 gene variant is not identified. These include TP53, PTEN, CDH1, and STK11. For instance, it has been demonstrated that 8% of women with very early-onset (less than 30 years of age) breast cancer who test negative for a variant in BRCA1 and BRCA2 have a variant in TP53.


Alterations in TP53, PTEN, CDH1, and STK11 are associated with hereditary cancer syndromes in which there is an increased risk for breast cancer; however, the risk for developing an invasive breast cancer associated with these syndromes varies. Some individuals with a pathogenic variant in one of these genes develop multiple primary cancers or bilateral cancers. Therefore, testing for variants in these 4 genes may also be useful when there is a suspicion of a hereditary susceptibility to breast cancer.


Lynch Syndrome

Lynch syndrome (also known as hereditary nonpolyposis colorectal cancer or HNPCC) is an autosomal dominant hereditary cancer syndrome associated with germline variants in the mismatch repair genes, MLH1, MSH2, MSH6, and PMS2. Deletions within the 3' end of the EPCAM gene, which lead to inactivation of the MSH2 promotor, have also been associated with Lynch syndrome.


Lynch syndrome is predominantly characterized by significantly increased risks for colorectal and endometrial cancer. The lifetime risk for colorectal cancer is highly variable and dependent on the gene involved. The risk for colorectal cancer-associated MLH1 and MSH2 variants (approximately 50%-80%) is generally higher than the risks associated with variants in the other Lynch syndrome-related genes. The lifetime risk for endometrial cancer (approximately 25%-60%) is also highly variable. Other malignancies within the tumor spectrum include gastric cancer, ovarian cancer, hepatobiliary and urinary tract carcinomas, and small bowel cancer. The lifetime risks for these cancers are less than 15%. Of the 4 mismatch repair genes, variants within the PMS2 gene confer the lowest risk for any of the tumors within the Lynch syndrome spectrum.


The National Comprehensive Cancer Network and the American Cancer Society provide recommendations regarding the medical management of individuals with HBOC and Lynch syndrome.

Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.

An interpretive report will be provided.

Interpretation Provides information to assist in interpretation of the test results

All detected alterations are evaluated according to American College of Medical Genetics and Genomics recommendations.(1) Variants are classified based on known, predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or known significance.

Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances

Clinical Correlations:

Some individuals who have a hereditary susceptibility to breast, endometrial, or colon cancer may have a variant that is not identified by this method (eg, promoter alterations, deep intronic alterations). The absence of a variant, therefore, does not eliminate the possibility of a hereditary susceptibility to breast cancer in the individual or family. For predictive testing, it is important to first document the presence of a gene variant in an affected family member.


Test results should be interpreted in the context of clinical findings, family history, and other laboratory data. Errors in the interpretation of results may occur if information given is inaccurate or incomplete. It is strongly recommended that patients undergoing predictive testing receive genetic counseling both prior to testing and after results are available.


Technical Limitations:

In some cases, DNA variants of undetermined significance may be identified. Due to the limitations of next generation sequencing, greater than 93% of insertions and deletions up to 20 bases and 43 bases, respectively, can be detected. If a diagnosis is still suspected, consider full gene sequencing using traditional Sanger methods. Single or multi-exon deletions as well as whole gene deletions will be detected by array comparative genomic hybridization (aCGH) or multiplex ligation-dependent probe amplification (MLPA). Rare alterations exist that could lead to false-negative or false-positive results.


If results obtained do not match the clinical findings, additional testing should be considered.


Evaluation Tools:

Multiple in-silico evaluation tools were used to assist in the interpretation of these results. These tools are updated regularly; therefore, changes to these algorithms may result in different predictions for a given alteration. Additionally, the predictability of these tools for the determination of pathogenicity is currently not validated.


Unless reported or predicted to cause disease, alterations found deep in the intron or alterations that do not result in an amino acid substitution are not reported. These and common alterations identified for this patient are available upon request.


Reclassification of Variants-Policy:

At this time, it is not standard practice for the laboratory to systematically re-review likely deleterious alterations or variants of uncertain significance that are detected and reported. The laboratory encourages health care providers to contact the laboratory at any time to learn how the status of a particular variant may have changed over time.

Clinical Reference Recommendations for in-depth reading of a clinical nature

1. Richards S, Aziz N, Bale S, et al: Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015 May;17(5):405-424

2. Lindor NM, McMaster ML, Lindor CJ, Greene MH; National Cancer Institute, Division of Cancer Prevention, Community Oncology and Prevention Trials Research Group. Concise handbook of familial cancer susceptibility syndromes - second edition. J Natl Cancer Inst Monogr. 2008;(38):1-93

3. Petrucelli N, Daley MB, Pal T: BRCA1- and BRCA2-associated hereditary breast and ovarian cancer. In:  Adams MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews (Internet). University of Washington, Seattle; 1998 Updated December 15, 2016. Accessed August 12, 2020. Available at www.ncbi.nlm.nih.gov/books/NBK1247/

4. Schneider K, Zelley K, Nichols KE, Garber J: Li-Fraumeni syndrome. In: Adams MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews (Internet). University of Washington, Seattle; 1999. Updated November 21, 2019. Accessed August 12, 2020 Available at www.ncbi.nlm.nih.gov/books/NBK1311/

5. Eng C: PTEN Hamartoma tumor syndrome.  In: Adams MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews (Internet). University of Washington, Seattle; 2001. Updated June 2, 2016. Accessed August 12, 2020 Available at www.ncbi.nlm.nih.gov/books/NBK1488/

6. Kaurah P, Huntsman DG: Hereditary diffuse gastric cancer. In: Adams MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews (Internet). University of Washington, Seattle; 2002. Updated March 22, 2018. Accessed August 12, 2020 Available at www.ncbi.nlm.nih.gov/books/NBK1139/

7. McGarrity TJ, Amos CI, Baker MJ: Peutz-Jeghers syndrome. In: Adams MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews (Internet). University of Washington, Seattle; 2001. Updated July 14, 2016. Accessed August 12, 2020 Available at www.ncbi.nlm.nih.gov/books/NBK1266/

8. Kohlmann W, Gruber SB: Lynch syndrome. In: Adams MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews (Internet). University of Washington, Seattle; 2004. Updated April 12, 2018. Accessed August 12, 2020 Available at www.ncbi.nlm.nih.gov/books/NBK1211/

9. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): Genetic/Familial High-Risk Assessment: Breast and Ovarian Version 1.2015. Accessed 6/1/2015. Available at www.nccn.org

10. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): Genetic/Familial High-Risk Assessment: Colorectal Version 2.2014. Accessed 6/1/2015. Available at www.nccn.org

11. McCuaig JM, Armel SR, Novokmet A, et al: Routine TP53 testing for breast cancer under age 30: ready for prime time? Fam Cancer. 2012 Dec;11(4):607-613

12. Saslow D, Boetes C, Burke W, et al: American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography. CA Cancer J Clin. 2007 Mar-Apr;57(2):75-89

13. Win AK, Young JP, Lindor NM, et al: Colorectal and other cancer risks for carriers and noncarriers from families with a DNA mismatch repair gene mutation: a prospective study. J Clin Oncol. 2012 Mar 20;30(9):958-964

14. Vaughn CP, Hart J, Samowitz WS, Swensen JJ: Avoidance of pseudogene interference in the detection of 3'deletions in PMS2. Hum Mutat. 2011;32:1063-1071

15. Clendenning M, Hampel H, LaJeunesse J, et al: Long-range PCR facilitates the identification of PMS2-specific mutations. Hum Mutat. 2006;27(5):490-495

Special Instructions Library of PDFs including pertinent information and forms related to the test