Misclassification of a frequent variant from PMS2CL pseudogene as a PMS2 loss of function variant in Brazilian patients.

Autor: Segura AVC; Clinical and Functional Genomics Group, International Research Center/CIPE, A.C.Camargo Cancer Center, 440 Taguá St, São Paulo, SP, 01508-010, Brazil., da Silva SIO; Clinical and Functional Genomics Group, International Research Center/CIPE, A.C.Camargo Cancer Center, 440 Taguá St, São Paulo, SP, 01508-010, Brazil., Santiago KM; Clinical and Functional Genomics Group, International Research Center/CIPE, A.C.Camargo Cancer Center, 440 Taguá St, São Paulo, SP, 01508-010, Brazil., Brianese RC; Clinical and Functional Genomics Group, International Research Center/CIPE, A.C.Camargo Cancer Center, 440 Taguá St, São Paulo, SP, 01508-010, Brazil., Carraro DM; Clinical and Functional Genomics Group, International Research Center/CIPE, A.C.Camargo Cancer Center, 440 Taguá St, São Paulo, SP, 01508-010, Brazil.; National Institute of Science and Technology in Oncogenomics and Therapeutic Innovation, São Paulo, Brazil., Torrezan GT; Clinical and Functional Genomics Group, International Research Center/CIPE, A.C.Camargo Cancer Center, 440 Taguá St, São Paulo, SP, 01508-010, Brazil. giovana.torrezan@accamargo.org.br.; National Institute of Science and Technology in Oncogenomics and Therapeutic Innovation, São Paulo, Brazil. giovana.torrezan@accamargo.org.br.
Jazyk: angličtina
Zdroj: Familial cancer [Fam Cancer] 2024 Nov; Vol. 23 (4), pp. 653-657. Date of Electronic Publication: 2024 Jun 20.
DOI: 10.1007/s10689-024-00411-1
Abstrakt: PMS2, a Lynch Syndrome gene, presents challenges in genetic testing due to the existence of multiple pseudogenes. This study aims to describe a series of cases harboring a variant in the PMS2CL pseudogene that has been incorrectly assigned to PMS2 with different nomenclatures. We reviewed data from 647 Brazilian patients who underwent multigene genetic testing at a single center to identify those harboring the PMS2 V1:c.2186_2187delTC or V2:c.2182_2184delACTinsG variants, allegedly located at PMS2 exon 13. Gene-specific PCR and transcript sequencing was performed. Among the 647 individuals, 1.8% (12) carried the investigated variants, with variant allele frequencies ranging from 15 to 34%. By visually inspecting the alignments, we confirmed that both V1 and V2 represented the same variant and through gene-specific PCR and PMS2 transcript analysis, we demonstrated that V1/V2 is actually located in the PMS2CL pseudogene. Genomic databases (ExAC and gnomAD) report an incidence of 2.5 - 5.3% of this variant in the African population. Currently, V1 is classified as "uncertain significance" and V2 as "conflicting" in ClinVar, with several laboratories classifying them as "pathogenic". We identified a frequent African PMS2CL variant in the Brazilian population that is misclassified as a PMS2 variant. It is likely that V1/V2 have been erroneously assigned to PMS2 in several manuscripts and by clinical laboratories, underscoring a disparity-induced matter. Considering the limitations of short-read NGS differentiating between certain regions of PMS2 and PMS2CL, using complementary methodologies is imperative to provide an accurate diagnosis.
(© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)
Databáze: MEDLINE
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