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Hum Mutat. 2020 Apr;41(4):749-752. doi: 10.1002/humu.23978. Epub 2020 Jan 16.

Reclassification of a frequent African-origin variant from PMS2 to the pseudogene PMS2CL.

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Lady Davis Institute, Segal Cancer Centre, Jewish General Hospital, Montréal, Québec, Canada.
Department of Human Genetics, McGill University, Montréal, Québec, Canada.


Genomic analysis has become a mainstay in the investigation of cancer patients, especially for those suspected of harboring a heritable cancer predisposition syndrome. With ubiquitous short-read next-generation sequencing (NGS) technologies, these analyses can be complicated by the inappropriate alignment of variants to homologous genomic regions or pseudogenes. Using distinct primer sets specific to the gene and pseudogene, a nonspecific primer set, and a highly gene-specific long-range polymerase chain reaction primer set, we have shown that in at least a subset of patients, the common African PMS2 variant NM_000535.5:c.2182_2184delACTinsG, classified as pathogenic in ClinVar, has been incorrectly assigned to PMS2 from its well-documented pseudogene, PMS2CL. This result is not only important for patients but also highlights a weakness in short-read NGS technologies and the racial inequity in genomic analysis.


Lynch syndrome; PMS2; PMS2CL; Sanger sequencing; next-generation sequencing; pseudogene


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