Multifactorial Likelihood Assessment of BRCA1 and BRCA2 Missense Variants Confirms That BRCA1:c.122A>Gp.His41Arg Is a Pathogenic MutationReportar como inadecuado




Multifactorial Likelihood Assessment of BRCA1 and BRCA2 Missense Variants Confirms That BRCA1:c.122A>Gp.His41Arg Is a Pathogenic Mutation - Descarga este documento en PDF. Documentación en PDF para descargar gratis. Disponible también para leer online.

Rare exonic, non-truncating variants in known cancer susceptibility genes such as BRCA1 and BRCA2 are problematic for genetic counseling and clinical management of relevant families. This study used multifactorial likelihood analysis and-or bioinformatically-directed mRNA assays to assess pathogenicity of 19 BRCA1 or BRCA2 variants identified following patient referral to clinical genetic services. Two variants were considered to be pathogenic Class 5. BRCA1:c.4484G> Cp.Arg1495Thr was shown to result in aberrant mRNA transcripts predicted to encode truncated proteins. The BRCA1:c.122A>Gp.His41Arg RING-domain variant was found from multifactorial likelihood analysis to have a posterior probability of pathogenicity of 0.995, a result consistent with existing protein functional assay data indicating lost BARD1 binding and ubiquitin ligase activity. Of the remaining variants, seven were determined to be not clinically significant Class 1, nine were likely not pathogenic Class 2, and one was uncertain Class 3.These results have implications for genetic counseling and medical management of families carrying these specific variants. They also provide additional multifactorial likelihood variant classifications as reference to evaluate the sensitivity and specificity of bioinformatic prediction tools and-or functional assay data in future studies.



Autor: Phillip J. Whiley, Michael T. Parsons, Jennifer Leary, Kathy Tucker, Linda Warwick, Belinda Dopita, Heather Thorne, Sunil R. Lakh

Fuente: http://plos.srce.hr/



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