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NCCN Guideline Updates for Hereditary Cancer Screening

Recent updates to the National Comprehensive Cancer Network® (NCCN) hereditary cancer testing guidelines recommend consideration of wider testing options for patients with colorectal cancer, and increased screening for patients with certain findings. The hereditary breast and ovarian cancer (HBOC) guidelines were also adjusted to recommend genetic testing if a family has a breast cancer diagnosis at a young age. Genetic testing helps clinicians understand what mutations led to a tumor and can also help identify if a person has inherited genetic variants that increase their risk for certain cancers.

Updated NCCN guidelines

Identifying hereditary cancers has opened up opportunities for more targeted treatments and prevention strategies for people with high-risk gene variants. NCCN guidelines for hereditary cancer testing are intended to help identify situations where a genetic variant dramatically increases lifetime cancer risk, makes a young diagnosis more likely, or improves treatment and prevention options. The NCCN committee relies on the latest peer-reviewed published data for established evidence of links between genetic variants and increased cancer risk to inform their updates.

One of the most well-known examples is hereditary breast cancer. NCCN guidelines have long recommended genetic testing for families at-risk because of the wide range of tailored treatment and prevention strategies available to individuals with high-risk variants of the BRCA1 and/or BRCA2 gene. The guidelines criteria continued to expand in version v1 2023 to be inclusive of people ages 45-49 who receive a breast cancer diagnosis. The committee considered new data to show that expanding guidelines may detect more patients with hereditary cancer risk, and those who might benefit from PARP inhibitor (PARPi) therapy.

New guidance for patients and families with breast cancer

Genetic testing is now clinically indicated if:

  • Personal or family history of breast cancer before age 50 in a first- or second-degree relative
  • Personal or family history of multiple primary breast cancers at any age
  • Personal or family history of prostate cancer (first-degree relative) AND close blood relative with either a) triple-negative breast cancer or b) male breast cancer

Previous recommendations used younger age limits, but new data indicates that broadening age guidelines for hereditary cancer screening helps identify more high-risk individuals.

New guidance for identifying hereditary cancer syndromes in patients with colorectal cancer

NCCN now recommends considering hereditary cancer testing for Lynch syndrome for all people with colorectal cancer (CRC). Previous guidelines recommended offering genetic testing to CRC patients under the age of 50 or those with certain tumor features.

This change comes following findings that 16% of tested colorectal cancer patients have a hereditary high-risk gene variant2,3 and promising early results for new treatments that effectively target colorectal cancers with a hereditary component.4

When Lynch syndrome is identified in a patient, NCCN also supports more proactive screening tailored to the high-risk gene variants involved, including:

  • Colonoscopy every 1-2 years, starting at age 20-25 or 10 years prior to the earliest family diagnosis for patients with high-risk MLH1, MSH2, and/or EPCAM gene variants
  • Colonoscopy every 1-3 years, starting at age 30-35 or 10 years prior to the earliest family diagnosis for patients with high-risk MSH6 and/or PMS2 gene variants
  • Upper gastrointestinal screening (esophagogastroduodenoscopy) every 2-4 years, starting at age 30-40 for patients with high-risk MLH1, MSH2, and/or MSH6 gene variants

Lynch syndrome

Lynch syndrome is one of the most common hereditary cancer syndromes. It involves variants in genes that help repair damaged DNA, such as MLH1, MSH2, MSH6 or PMS2, as well as an additional gene called EPCAM. If a person has Lynch syndrome, it is likely that they inherited it from one of their parents, and each of their children has a 50% chance of inheriting it.

People with Lynch syndrome are at increased risk for early age colorectal cancer, as well as cancers in the lining of the stomach, uterus, and other organs. The lifetime colorectal cancer risk for a person with Lynch syndrome is up to 78%.1

People with Lynch syndrome often benefit from early and more frequent cancer screening, and in some cases may choose preventative medications or surgeries to reduce their cancer risk. If Lynch syndrome is identified when a person is diagnosed with cancer, it often impacts the treatments their oncologist recommends.

Understanding hereditary cancer

In order for a tumor to develop, the cells involved must have multiple genetic changes to key genes. Usually, the majority of these changes occur after a person is born, and are known as somatic mutations, meaning genetic changes in cells of the body.

In up to 10% of cancer cases, a risk-increasing genetic change was inherited from a parent and present at birth.5 Hereditary changes like this are often known as gene variants because they are a variation of a particular gene. They are also referred to as germline variants or mutations because they are present in a person’s eggs or sperm.

Many gene variants are harmless and part of normal variation that makes each person unique. However, some have been found to increase a person’s risk of developing certain kinds of cancer. A person carrying a risk-increasing variant makes cancer more likely because fewer somatic mutations are necessary for a tumor to form.

Hereditary cancer occurs when a person with a risk-increasing gene variant develops cancer. Hereditary cancers often run in families, but may appear as different types of cancer in different family members depending on which genes are involved. When high-risk variants in a gene or set of genes are common, it is often known as a hereditary cancer syndrome.

The future of hereditary cancer screening

As genetic screening for hereditary cancer continues to yield benefits for patients, many researchers and clinicians envision a world where broad screening becomes a standard part of patient care. A recent study of nearly 27,000 Nevada residents found that 1.3%, or roughly 350 people, carried a gene variant that significantly increased their risk of developing cancer. Of the affected people, 21.9% already had cancer, and 90% had not known about their risk until testing.

The new NCCN guidelines encourage genetic screening for a wider range of patients and move a step closer toward broad population screening.

Hereditary cancer screening with Empower™

If a patient has cancer, it appears to run in their family, or they are simply curious about their cancer risk, genetic testing can help them learn more about their hereditary risk for certain cancers.

The Empower™ Hereditary Cancer Test identifies genetic risk factors for a wide range of hereditary cancers. It helps people learn more about genetic variants that can impact their future cancer risk or could have been involved in the development of a tumor.

Jeffery Weitzel, MD, a hereditary cancer expert, recently joined Natera’s team as a Vice President of Medical Affairs. Click here to hear Dr. Weitzel speak about the recent NCCN update and the research that spurred it.


1Järvinen HJ et al. Ten years after mutation testing for Lynch syndrome: cancer incidence and outcome in mutation-positive and mutation-negative family members. J Clin Oncol. 2009;27(28):4793-4797. doi:10.1200/JCO.2009.23.7784

2Yurgelun MB et al. Cancer Susceptibility Gene Mutations in Individuals With Colorectal Cancer. J Clin Oncol. 2017;35(10):1086-1095. doi:10.1200/JCO.2016.71.0012

3Pearlman R et al. Prevalence and Spectrum of Germline Cancer Susceptibility Gene Mutations Among Patients With Early-Onset Colorectal Cancer. JAMA Oncol. 2017;3(4):464-471. doi:10.1001/jamaoncol.2016.5194

4Cercek A et al. PD-1 Blockade in Mismatch Repair–Deficient, Locally Advanced Rectal Cancer. N Engl J Med. 2022;386(25):2363-2376. doi:10.1056/NEJMoa2201445

5The Genetics of Cancer. National Cancer Institute. Published April 22, 2015. Accessed August 18, 2022.