interference leading to erroneous identification of a pathogenic variant in Black patients.

This study investigates the frequency of a clinically reported variant in , NM_000535.7:c.2523G>A p.(W841∗), from next-generation sequencing studies in 2 racially diverse cohorts. We identified clinical reports of the c.2523G>A p.(W841∗) variant in the National Precision Oncology Program's somatic testing database ( = 25,168). We determined frequency of the variant in germline exome sequencing from the Penn Medicine BioBank ( = 44,256) and in gnomAD. The c.2523G>A p.(W841∗) was identified as a homozygous variant on tumor testing in an adult patient of self-identified Black race/ethnicity with no evidence of constitutional mismatch repair deficiency. The variant was clinically reported on 35 total tumor and liquid biopsy tests (0.1%), and all individuals with the variant were of self-identified Black race/ethnicity (0.6% of  = 5787). In individuals of African genetic ancestry (AFR), the variant's germline frequency was reported to be 0.2% and 1.3% in the Penn Medicine BioBank (PMBB) and gnomAD, respectively. The variant cannot be found in any individuals of European genetic ancestry (EUR) from either of the databases. The variant is found in a region of with 100% homology to the pseudogene. c.2523G>A p.(W841∗), when identified, is typically an African-ancestry-specific pseudogene variant, which should be recognized to prevent misdiagnosis of Lynch syndrome in Blacks.