This case is part of our ongoing Genetic Testing Challenges in Oncology series, which examines how gaps in genetic testing and communication can delay accurate diagnoses. In this case, standard DNA-only sequencing nearly missed a hereditary cancer syndrome hiding deep inside a single gene.
An Incidental Finding Uncovers a Missed Diagnosis
A pathology screening program connected a 45-year-old man with a genetic counselor after he underwent a bone marrow biopsy for anemia. The genetic counselor noticed a somatic BRCA2 variant at a variant allele frequency of 31.7 percent, a level high enough to suggest the variant might be germline in origin.
A review of the patient’s records revealed something else: surgeons had removed numerous neurofibromas from his body over the years, and doctors had clinically diagnosed him with neurofibromatosis type 1 (NF1). The patient did not know about this diagnosis, and he had never received germline genetic testing or a referral to a medical geneticist.
DNA and RNA Sequencing Reveal What Standard Testing Missed
The genetic counselor ordered germline testing using both DNA and RNA sequencing. Results confirmed that the pathogenic BRCA2 variant was germline. They also identified a second variant deep within a non-coding intron of the NF1 gene, more than 11,500 base pairs in — a location standard DNA-only testing would not have detected.
The lab initially classified the NF1 variant as a variant of uncertain significance. Months later, the lab upgraded the classification to likely pathogenic, prompting the patient to return to clinic so his children could be screened.
Genetic counselors found that the patient’s young daughter, who had café-au-lait spots, carried the NF1 variant and referred her to an NF1 clinic. The case also uncovered a false-negative result in the patient’s sister: DNA-only testing had shown her as negative for NF1, but RNA sequencing revealed she carried the familial variant after all.
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