In Silico Systems Biology Analysis of Variants of Uncertain Significance in Lynch Syndrome Supports the Prioritization of Functional Molecular Validation

Lynch syndrome (LS) is a genetic condition secondary to germline alterations in the DNA mismatch repair (MMR) genes with 30% of changes being variants of uncertain significance (VUS). Our aim was to perform an reclassification of VUS from a large single institutional cohort that will help prioritizi...

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Published in:Cancer prevention research (Philadelphia, Pa.) Pa.), 2017-10, Vol.10 (10), p.580-587
Main Authors: Borras, Ester, Chang, Kyle, Pande, Mala, Cuddy, Amanda, Bosch, Jennifer L, Bannon, Sarah A, Mork, Maureen E, Rodriguez-Bigas, Miguel A, Taggart, Melissa W, Lynch, Patrick M, You, Y Nancy, Vilar, Eduardo
Format: Article
Language:English
Subjects:
Adolescent
Adult
Aged
Cohort Studies
Colorectal Neoplasms, Hereditary Nonpolyposis - genetics
Colorectal Neoplasms, Hereditary Nonpolyposis - pathology
Computer Simulation
DNA Mismatch Repair - genetics
DNA-Binding Proteins - genetics
Female
Genetic Variation
Humans
Male
Middle Aged
Young Adult
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Summary:Lynch syndrome (LS) is a genetic condition secondary to germline alterations in the DNA mismatch repair (MMR) genes with 30% of changes being variants of uncertain significance (VUS). Our aim was to perform an reclassification of VUS from a large single institutional cohort that will help prioritizing functional validation. A total of 54 VUS were detected with 33 (61%) novel variants. We integrated family history, pathology, and genetic information along with supporting evidence from eight different tools at the RNA and protein level. Our assessment allowed us to reclassify 54% (29/54) of the VUS as probably damaging, 13% (7/54) as possibly damaging, and 28% (15/54) as probably neutral. There are more than 1,000 VUS reported in MMR genes and our approach facilitates the prioritization of further functional efforts to assess the pathogenicity to those classified as probably damaging. .
ISSN:1940-6207
1940-6215
DOI:10.1158/1940-6207.CAPR-17-0058