Pathogenic Variant Carriers Missed by Current Genetic Testing

Current guidelines recommend genetic testing for people who have a personal or family history of cancer that indicates they might be at an increased risk of harboring a pathogenic familial variant, but this approach could miss people who lack any personal or family history.

Recent advancements in next-generation sequencing have greatly expanded the use of multi-gene testing panels in clinical diagnosis and management. Multi-gene panels are more sensitive and efficient than traditional testing paradigms and are increasingly more affordable. Furthermore, multi-gene panels increase the likelihood of detecting an underlying germline genetic component in diseases with genetic heterogeneity, such as cancer.


A team of scientists working under the auspices of Color Genomics, Inc (Burlingame, CA, USA) retrospective studied included 23,179 individuals who had Color Hereditary Cancer Test results reported between May 2016 and September 2017. The Color Hereditary Cancer Test was used to analyze 30 genes in which pathogenic variants have been associated with an elevated risk of hereditary cancer, including breast, ovarian, uterine/endometrial, colorectal, melanoma, pancreatic, prostate, and stomach.

DNA was extracted from blood or saliva samples and purified using the Chemagic DNA Extraction Kit automated on the Hamilton STAR and the Perkin Elmer Chemagic Liquid Handler instruments. The genes analyzed encompass BRCA1, BRCA2, CDKN2A, PTEN, TP53, and more. Target enrichment was performed with an automated Hamilton STAR hybrid capture procedure using SureSelect XT probes before being loaded onto the NextSeq 500/550 instrument for 150-bp paired-end sequencing.

The team identified 2,811 pathogenic variants in 2,698 individuals, an overall pathogenic variant frequency of 11.6%. Pathogenic variants in BRCA1 and BRCA2 accounted for nearly a third of all positive results, while pathogenic variants linked to Lynch syndrome accounted for another 7.0% of results. They noted that pathogenic variants in BRCA1 or BRCA2 could be found across ethnic groups. While most individuals with a positive result harbored only a single pathogenic variant, a small number had two or more pathogenic variants, such as in BRCA1 or BRCA2 and in another cancer-linked gene. Of the 18,176 individuals in their cohort with sufficient health histories, 61.3% met criteria for genetic testing for breast, ovarian, colorectal, or gastric cancer and 38.7% did not.

Among those patients who did not meet testing criteria, but who underwent testing anyway, the scientists reported an 8.2% pathogenic frequency and, of those, 21.7% had pathogenic variants in genes with well-established testing criteria. That means that of the 749 individuals they identified with a pathogenic variant in BRCA1, BRCA2, TP53, or PTEN, 18.4% would not have met testing guidelines for breast and ovarian cancer. Similarly, slightly more than a third of the individuals they identified with Lynch syndrome-linked variants would not have met testing criteria. The study was published on June 11, 2019, in the Journal of Molecular Diagnostics.

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