PMS2CL interference leading to erroneous identification of a pathogenic PMS2 variant in Black patients

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This study investigates the frequency of a clinically reported variant in PMS2, NM_000535.7:c.2523G>A p.(W841*), from next-generation sequencing studies in two racially diverse cohorts. We identified clinical reports of the PMS2 c.2523G>A p.(W841*)variant in the National Precision Oncology Program’s (NPOP) somatic testing database (n=25,168). We determined frequency of the variant in germline exome sequencing (ES) from the Penn Medicine Biobank (PMBB, n=44,256) and in gnomAD. The PMS2 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 (CMMR-D). 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 n=5787). In the PMBB and gnomAD, the germline frequency of the variant was reported to be 0.2% and 1.3% in individuals of African genetic ancestry (AFR), respectively, and not found in any individuals of European genetic ancestry (EUR). The variant is found in a region of PMS2 with 100% homology to the PMS2CL pseudogene. PMS2 c.2523G>A p.(W841*)when identified is typically an African ancestry specific PMS2CL pseudogene variant which should be recognized to prevent misdiagnosis of Lynch syndrome in Blacks.

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