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Adding In Silico Assessment of Potential Splice Aberration to the Integrated Evaluation of BRCA Gene Unclassified Variants.

ABSTRACT: Clinical mutation screening of the cancer susceptibility genes BRCA1 and BRCA2 generates many unclassified variants (UVs). Most of these UVs are either rare missense substitutions or nucleotide substitutions near the splice junctions of the protein coding exons. Previously, we developed a quantitative method for evaluation of BRCA gene UVs-the "integrated evaluation"-that combines a sequence analysis-based prior probability of pathogenicity with patient and/or tumor observational data to arrive at a posterior probability of pathogenicity. One limitation of the sequence analysis-based prior has been that it evaluates UVs from the perspective of missense substitution severity but not probability to disrupt normal mRNA splicing. Here, we calibrated output from the splice-site fitness program MaxEntScan to generate spliceogenicity-based prior probabilities of pathogenicity for BRCA gene variants; these range from 0.97 for variants with high probability to damage a donor or acceptor to 0.02 for exonic variants that do not impact a splice junction and are unlikely to create a de novo donor. We created a database http://priors.hci.utah.edu/PRIORS/ that provides the combined missense substitution severity and spliceogenicity-based probability of pathogenicity for BRCA gene single-nucleotide substitutions. We also updated the BRCA gene Ex-UV LOVD, available at http://hci-exlovd.hci.utah.edu, with 77 re-evaluable variants.

SUBMITTER: Vallee MP

PROVIDER: S-EPMC4907813 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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Adding In Silico Assessment of Potential Splice Aberration to the Integrated Evaluation of BRCA Gene Unclassified Variants.

Vallée Maxime P MP Di Sera Tonya L TL Nix David A DA Paquette Andrew M AM Parsons Michael T MT Bell Russel R Hoffman Andrea A Hogervorst Frans B L FB Goldgar David E DE Spurdle Amanda B AB Tavtigian Sean V SV

Human mutation 20160415 7

Clinical mutation screening of the cancer susceptibility genes BRCA1 and BRCA2 generates many unclassified variants (UVs). Most of these UVs are either rare missense substitutions or nucleotide substitutions near the splice junctions of the protein coding exons. Previously, we developed a quantitative method for evaluation of BRCA gene UVs-the "integrated evaluation"-that combines a sequence analysis-based prior probability of pathogenicity with patient and/or tumor observational data to arrive ...[more]

PMID: 26913838

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Project description:Introduction: Recent advances in sequencing technologies have significantly increased our capability to acquire large amounts of genetic data. However, the clinical relevance of the generated data continues to be challenging particularly with the identification of Variants of Uncertain Significance (VUSs) whose pathogenicity remains unclear. In the current report, we aim to evaluate the clinical relevance and the pathogenicity of VUSs in DNA repair genes among Tunisian breast cancer families. Methods: A total of 67 unsolved breast cancer cases have been investigated. The pathogenicity of VUSs identified within 26 DNA repair genes was assessed using different in silico prediction tools including SIFT, PolyPhen2, Align-GVGD and VarSEAK. Effects on the 3D structure were evaluated using the stability predictor DynaMut and molecular dynamics simulation with NAMD. Family segregation analysis was also performed. Results: Among a total of 37 VUSs identified, 11 variants are likely deleterious affecting ATM, BLM, CHEK2, ERCC3, FANCC, FANCG, MSH2, PMS2 and RAD50 genes. The BLM variant, c.3254dupT, is novel and seems to be associated with increased risk of breast, endometrial and colon cancer. Moreover, c.6115G>A in ATM and c.592+3A>T in CHEK2 were of keen interest identified in families with multiple breast cancer cases and their familial cosegregation with disease has been also confirmed. In addition, functional in silico analyses revealed that the ATM variant may lead to protein immobilization and rigidification thus decreasing its activity. We have also shown that FANCC and FANCG variants may lead to protein destabilization and alteration of the structure compactness which may affect FANCC and FANCG protein activity. Conclusion: Our findings revealed that VUSs in DNA repair genes might be associated with increased cancer risk and highlight the need for variant reclassification for better disease management. This will help to improve the genetic diagnosis and therapeutic strategies of cancer patients not only in Tunisia but also in neighboring countries.

Project description:Primary progressive aphasia, a neurodegenerative syndrome, presents mainly with language impairment. Both semantic and logopenic variants are fluent variants of primary progressive aphasia. Before the research criteria of primary progressive aphasia were proposed, progressive fluent aphasias, such as progressive anomic aphasia, transcortical sensory aphasia and Wernicke's aphasia, were reported as classical progressive fluent aphasias seen in Alzheimer's disease. However, since the research criteria of primary progressive aphasia were established, classical fluent variants (other than semantic and logopenic variants) have been neglected and have not been included in the current classification of primary progressive aphasia. This study aimed to determine whether unclassified fluent variants (other than semantic and logopenic variants) can be manifestations of primary progressive aphasia. This study also reconfirmed the characteristics of classical progressive fluent aphasia, such as progressive anomic aphasia, progressive transcortical sensory aphasia and progressive Wernicke's aphasia as unclassified fluent variants of primary progressive aphasia, using comparison with the current model of primary progressive aphasia. Twelve consecutive patients with an unclassified fluent variant other than semantic or logopenic variant underwent language, neurological, neuropsychological and neuroimaging (MRI and single-photon emission computed tomography) testing. Based on comprehensive language tests, we redefined the diagnoses as primary progressive anomic aphasia (n = 8), primary progressive transcortical sensory aphasia (n = 3) and primary progressive Wernicke's aphasia (n = 1). Anomic aphasia was characterized by anomia but preserved repetition and comprehension; transcortical sensory aphasia by relatively preserved repetition but poor word comprehension; and Wernicke's aphasia by poor repetition and word comprehension. In patients with anomic aphasia, voxel-based morphometry of MRI data revealed cortical atrophy, which was most prominent in the temporoparietal lobes, with no obvious lateralization; in two-thirds of patients with transcortical sensory aphasia and in one patient with Wernicke's aphasia, it revealed atrophy, predominantly in the left temporoparietal lobe. Statistical analysis of single-photon emission computed tomography using three-dimensional stereotactic surface projections revealed patterns of left-sided hypoperfusion in the majority of patients. The temporal and parietal lobes were involved in all cases; the degree of hypoperfusion was higher in patients with transcortical sensory aphasia or Wernicke's aphasia than in patients with anomic aphasia. The present study demonstrated the clinical and imaging features of 12 patients with an unclassified fluent variant of primary progressive aphasia, which we redefined as primary progressive anomic aphasia, primary progressive transcortical sensory aphasia and primary progressive Wernicke's aphasia. Classical fluent variants other than semantic and logopenic variants can be found in primary progressive aphasia.

Dataset Information

Adding In Silico Assessment of Potential Splice Aberration to the Integrated Evaluation of BRCA Gene Unclassified Variants.

Publications

Adding In Silico Assessment of Potential Splice Aberration to the Integrated Evaluation of BRCA Gene Unclassified Variants.

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