Multifactorial likelihood assessment of BRCA1 and BRCA2 missense variants confirms that BRCA1:c.122A>G(p.His41Arg) is a pathogenic mutation.
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.
QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia ; School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, Queensland, Australia.
Phillip J
PJ
Whiley
QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
Michael T
MT
Parsons
Familial Cancer Service, Westmead Institute for Cancer Research, University of Sydney at Westmead Millennium Institute, Westmead Hospital, Sydney, NSW, Australia.
Jennifer
J
Leary
Hereditary Cancer Clinic, Prince of Wales Hospital, Randwick, Sydney, NSW, Australia.
Kathy
K
Tucker
Genetics Department, The Canberra Hospital, Canberra, ACT, Australia.
Linda
L
Warwick
Genetics Department, The Canberra Hospital, Canberra, ACT, Australia.
Belinda
B
Dopita
kConFab, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
Heather
H
Thorne
The University of Queensland, UQ Centre for Clinical Research and School of Medicine, and Pathology Queensland, The Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia.
Sunil R
SR
Lakhani
Huntsman Cancer Institute and Department of Dermatology, University of Utah, Salt Lake City, Utah, United States of America.
David E
DE
Goldgar
School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, Queensland, Australia.
Melissa A
MA
Brown
QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
Amanda B
AB
Spurdle
D017398:Alternative Splicing / Q000235:genetics; D019313:BRCA1 Protein / Q000235:genetics*; D024682:BRCA2 Protein / Q000235:genetics*; D019295:Computational Biology; D005091:Exons / Q000235:genetics; D020022:Genetic Predisposition to Disease; D006801:Humans; D016013:Likelihood Functions; D020412:Multifactorial Inheritance / Q000235:genetics*; D020125:Mutation, Missense / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015203:Reproducibility of Results; D017384:Sequence Deletion / Q000235:genetics
D019313:BRCA1 Protein; D024682:BRCA2 Protein; D012333:RNA, Messenger