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Sweet K.,Clinical Cancer Genetics Program | Sweet K.,Comprehensive Cancer Center | Sweet K.,Ohio State University | Senter L.,Clinical Cancer Genetics Program | And 8 more authors.
Breast Cancer Research and Treatment | Year: 2010

The majority of pathogenic mutations in BRCA1 result in a truncated protein. Although most missense changes in BRCA1 are of unknown functional significance, a handful of deleterious missense mutations have been identified. The majority of these occur in splice sites or highly conserved protein domains. Previously, we developed a predictive model, VUS Predict, to classify BRCA variants of uncertain significance as neutral or deleterious. It uses evolutionary prediction algorithms together with clinical information from cancer pathology reports and BRCA genetic testing results. Because of the higher probability that missense changes occurring in conserved BRCA1 domains are of pathogenic significance, we identified all individuals in our cohort who had been tested for BRCA1 and BRCA2 mutations who had missense changes in the BRCA1 ring finger domain and sought to classify those changes. We applied VUS Predict to three previously uncharacterized variants and four missense changes known to be deleterious. Two variants, L22S and T37K, were predicted to be deleterious and one variant, K45Q, was predicted to be neutral by VUS Predict. The mutations C39R, C44Y, C44S, and C61G were confirmed as deleterious. © 2009 Springer Science+Business Media, LLC.

Gammon A.,Huntsman Cancer Institute | Jasperson K.,Huntsman Cancer Institute | Pilarski R.,Clinical Cancer Genetics Program | Prior T.W.,Ohio State University | Kuwada S.,University of Hawaii at Manoa
Clinical Genetics | Year: 2013

We present the first known case of somatic PTEN mosaicism causing features of Cowden syndrome (CS) and inheritance in the subsequent generation. A 20-year-old woman presented for genetics evaluation with multiple ganglioneuromas of the colon. On examination, she was found to have a thyroid goiter, macrocephaly, and tongue papules, all suggestive of CS. However, her reported family history was not suspicious for CS. A deleterious PTEN mutation was identified in blood lymphocytes, 966A>G, 967delA. Genetic testing was recommended for her parents. Her 48-year-old father was referred for evaluation and was found to have macrocephaly and a history of Hashimoto's thyroiditis, but no other features of CS. Site-specific genetic testing carried out on blood lymphocytes showed mosaicism for the same PTEN mutation identified in his daughter. Identifying PTEN mosaicism in the proband's father had significant implications for the risk assessment/genetic testing plan for the rest of his family. His result also provides impetus for somatic mosaicism in a parent to be considered when a de novo PTEN mutation is suspected. © 2012 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

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