Alleviating misclassified germline variants in underrepresented populations: A strategy using popmax.
Genet Med
; 26(6): 101124, 2024 06.
Article
em En
| MEDLINE
| ID: mdl-38522067
ABSTRACT
PURPOSE:
Germline variant interpretation often depends on population-matched control cohorts. This is not feasible for population groups that are underrepresented in current population reference databases.METHODS:
We classify germline variants with population-matched controls for 2 ancestrally diverse cohorts of patients 132 early-onset or familial colorectal carcinoma patients from Singapore and 100 early-onset colorectal carcinoma patients from the United States. The effects of using a population-mismatched control cohort are simulated by swapping the control cohorts used for each patient cohort, with or without the popmax computational strategy.RESULTS:
Population-matched classifications revealed a combined 62 pathogenic or likely pathogenic (P/LP) variants in 34 genes across both cohorts. Using a population-mismatched control cohort resulted in misclassification of non-P/LP variants as P/LP, driven by the absence of ancestry-specific rare variants in the control cohort. Popmax was more effective in alleviating misclassifications for the Singapore cohort than the US cohort.CONCLUSION:
Underrepresented population groups can suffer from higher rates of false-positive P/LP results. Popmax can partially alleviate these misclassifications, but its efficacy still depends on the degree with which the population groups are represented in the control cohort.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Neoplasias Colorretais
/
Mutação em Linhagem Germinativa
Limite:
Female
/
Humans
/
Male
País/Região como assunto:
America do norte
/
Asia
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article