TY - JOUR
T1 - Assessment of incidental findings in 232 whole-exome sequences from the Baylor-Hopkins Center for Mendelian Genomics
AU - Jurgens, Julie
AU - Ling, Hua
AU - Hetrick, Kurt
AU - Pugh, Elizabeth
AU - Schiettecatte, Francois
AU - Doheny, Kimberly
AU - Hamosh, Ada
AU - Avramopoulos, Dimitri
AU - Valle, David
AU - Sobreira, Nara
N1 - Publisher Copyright:
© American College of Medical Genetics and Genomics.
PY - 2015/10/1
Y1 - 2015/10/1
N2 - Purpose:In March 2013 the American College of Medical Genetics and Genomics published a list of 56 genes with the recommendation that pathogenic and likely pathogenic variants detected incidentally by clinical sequencing be reported to patients. As an initial step in determining the practical consequences of this recommendation in the research setting, we searched for variants in these genes in 232 whole-exome sequences from the Baylor-Hopkins Center for Mendelian Genomics.Methods:We identified rare, nonsynonymous, and splicing single-nucleotide variants and insertions/deletions and assessed variant classification using the Human Gene Mutation, Emory, and ClinVar databases. We analyzed the burden of mutation in each of the 56 genes and determined which variants should be reported to patients.Results:Our filtering resulted in 249 distinct variants, with a mean of 1.69 variants per individual. Half of these were novel missense mutations not classified by any of the three reference databases. Of 101 variants listed in the Human Gene Mutation Database, 48 were also in ClinVar and 3 were also in Emory; half of these shared variants were classified discordantly between databases. Some genes consistently had greater variation than others. In total, 0.86% of individuals had a reportable incidental variant.Conclusion:These observations demonstrate some current challenges of assessing phenotypic consequences of incidental variants for counseling patients.
AB - Purpose:In March 2013 the American College of Medical Genetics and Genomics published a list of 56 genes with the recommendation that pathogenic and likely pathogenic variants detected incidentally by clinical sequencing be reported to patients. As an initial step in determining the practical consequences of this recommendation in the research setting, we searched for variants in these genes in 232 whole-exome sequences from the Baylor-Hopkins Center for Mendelian Genomics.Methods:We identified rare, nonsynonymous, and splicing single-nucleotide variants and insertions/deletions and assessed variant classification using the Human Gene Mutation, Emory, and ClinVar databases. We analyzed the burden of mutation in each of the 56 genes and determined which variants should be reported to patients.Results:Our filtering resulted in 249 distinct variants, with a mean of 1.69 variants per individual. Half of these were novel missense mutations not classified by any of the three reference databases. Of 101 variants listed in the Human Gene Mutation Database, 48 were also in ClinVar and 3 were also in Emory; half of these shared variants were classified discordantly between databases. Some genes consistently had greater variation than others. In total, 0.86% of individuals had a reportable incidental variant.Conclusion:These observations demonstrate some current challenges of assessing phenotypic consequences of incidental variants for counseling patients.
KW - American College of Medical Genetics and Genomics recommendations
KW - incidental findings
KW - secondary findings
KW - variant classification
KW - whole-exome sequencing
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U2 - 10.1038/gim.2014.196
DO - 10.1038/gim.2014.196
M3 - Article
C2 - 25569433
AN - SCOPUS:84939157303
SN - 1098-3600
VL - 17
SP - 782
EP - 788
JO - Genetics in Medicine
JF - Genetics in Medicine
IS - 10
ER -