Multifactorial likelihood assessment of BRCA1 and BRCA2 missense variants confirms that BRCA1:c.122A>G(p.His41Arg) is a pathogenic mutation

Whiley, Phillip J., Parsons, Michael T., Leary, Jennifer, Tucker, Kathy, Warwick, Linda, Dopita, Belinda, Thorne, Heather, Lakhani, Sunil R., Goldgar, David E., Brown, Melissa A. and Spurdle, Amanda B. (2014) Multifactorial likelihood assessment of BRCA1 and BRCA2 missense variants confirms that BRCA1:c.122A>G(p.His41Arg) is a pathogenic mutation. PloS One, 9 1: 1-10. doi:10.1371/journal.pone.0086836

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Author Whiley, Phillip J.
Parsons, Michael T.
Leary, Jennifer
Tucker, Kathy
Warwick, Linda
Dopita, Belinda
Thorne, Heather
Lakhani, Sunil R.
Goldgar, David E.
Brown, Melissa A.
Spurdle, Amanda B.
Title Multifactorial likelihood assessment of BRCA1 and BRCA2 missense variants confirms that BRCA1:c.122A>G(p.His41Arg) is a pathogenic mutation
Formatted title
Multifactorial likelihood assessment of BRCA1 and BRCA2 missense variants confirms that BRCA1:c.122A>G(p.His41Arg) is a pathogenic mutation
Journal name PloS One   Check publisher's open access policy
ISSN 1932-6203
Publication date 2014-01-28
Sub-type Article (original research)
DOI 10.1371/journal.pone.0086836
Open Access Status DOI
Volume 9
Issue 1
Start page 1
End page 10
Total pages 10
Editor Paolo Peterlongo
Place of publication San Francisco, CA, United States
Publisher Public Library of Science
Language eng
Formatted abstract
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> C(p.Arg1495Thr) was shown to result in aberrant mRNA transcripts predicted to encode truncated proteins. The BRCA1:c.122A>G(p.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.
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

 
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Created: Fri, 14 Feb 2014, 20:01:41 EST by Mrs Louise Nimwegen on behalf of School of Chemistry & Molecular Biosciences