Following current genetic screening guidelines may cause clinicians to miss as many as 40% of patients with high-risk hereditary cancer syndromes, according to research presented at the AACR Annual Meeting 2023.

Researchers used whole-exome sequencing to identify patients with Lynch syndrome or hereditary breast and ovarian cancer syndrome (HBOC) in a cohort of more than 44,000 patients. 

Of the 550 patients with either syndrome, 39.2% would not have been found using National Comprehensive Cancer Network (NCCN) guidelines for genetic screening.

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For this study, researchers used data from the TAPESTRY trial ( Identifier: NCT05212428), which is enrolling patients at 3 Mayo Clinic practices across the United States. 

The study cohort included 44,306 patients who underwent whole-exome sequencing, 550 of whom had HBOC or Lynch syndrome. Patients with HBOC had variants in BRCA1 and BRCA2, and patients with Lynch syndrome had variants in MLH1, MSH2, MSH6, PMS2, and EPCAM.

A total of 387 patients had HBOC, and 163 had Lynch syndrome. The overall prevalence of both was 1.24%. 

There was a personal history of cancer in 47.3% of patients with HBOC and 44.2% of patients with Lynch syndrome. Cancer types included breast (35.1% and 10.2%, respectively), ovarian (7.1% and 1.1%), colorectal (4.3% and 26.1%), and uterine (1.4% and 13.6%). 

More than half of patients with HBOC or Lynch syndrome (52.1%) did not have prior knowledge of their condition, including 49.1% of those with HBOC and 59.3% of those with Lynch syndrome. 

Among patients with either hereditary cancer syndrome, 39.2% did not meet NCCN criteria for genetic screening. The proportion of patients who didn’t meet criteria was higher among those with Lynch syndrome (56.2%) than among those with HBOC (32%). 

The most common reasons for not meeting NCCN criteria were that patients had no personal history of cancer (63.3%), they had an insufficient number of relatives with cancer (60.5%), or they or their relatives had cancers not related to a hereditary cancer syndrome (58.6%).

“[The NCCN] criteria were created at a time when genetic testing was cost-prohibitive and thus aimed to identify those at the greatest chance of being a mutation carrier in the absence of population-wide whole-exome sequencing,” study author N. Jewel Samadder, MD, of the Mayo Clinic Comprehensive Cancer Center in Phoenix, Arizona, said in a statement.

“However, these conditions are poorly identified in current practice, and many patients are not aware of their cancer risk. This study shows the feasibility of providing whole-exome sequencing to large populations of patients within an integrated health system and diagnosing individuals who have an inherited susceptibility to cancer.” 

The researchers also found that, among patients with HBOC or Lynch syndrome who did meet NCCN guidelines, 34% were not aware of their diagnosis. This suggests that NCCN guidelines may be underutilized in practice.  

Disclosures: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.


1. Gay E, Samadder NJ, Bublitz M, et al. Genetic screening in a tertiary medical center identifies carriers of cancer predisposition diseases that would be missed by clinical guidelines. AACR 2023. April 14-19, 2023. Abstract 5768.

2. Exome sequencing identifies individuals with cancer predisposition syndromes missed by current screening guidelines. News release. American Association for Cancer Research. Published April 18, 2023.