RT Journal Article
SR Electronic
T1 Analysis of missense variation in human BRCA1 in the context of interspecific sequence variation
JF Journal of Medical Genetics
JO J Med Genet
FD BMJ Publishing Group Ltd
SP 492
OP 507
DO 10.1136/jmg.2003.015867
VO 41
IS 7
A1 V Abkevich
A1 A Zharkikh
A1 A M Deffenbaugh
A1 D Frank
A1 Y Chen
A1 D Shattuck
A1 M H Skolnick
A1 A Gutin
A1 S V Tavtigian
YR 2004
UL http://jmg.bmj.com/content/41/7/492.abstract
AB Introduction: Interpretation of results from mutation screening of tumour suppressor genes known to harbour high risk susceptibility mutations, such as APC, BRCA1, BRCA2, MLH1, MSH2, TP53, and PTEN, is becoming an increasingly important part of clinical practice. Interpretation of truncating mutations, gene rearrangements, and obvious splice junction mutations, is generally straightforward. However, classification of missense variants often presents a difficult problem. From a series of 20 000 full sequence tests of BRCA1 carried out at Myriad Genetic Laboratories, a total of 314 different missense changes and eight in-frame deletions were observed. Before this study, only 21 of these missense changes were classified as deleterious or suspected deleterious and 14 as neutral or of little clinical significance. Methods: We have used a combination of a multiple sequence alignment of orthologous BRCA1 sequences and a measure of the chemical difference between the amino acids present at individual residues in the sequence alignment to classify missense variants and in-frame deletions detected during mutation screening of BRCA1. Results: In the present analysis we were able to classify an additional 50 missense variants and two in-frame deletions as probably deleterious and 92 missense variants as probably neutral. Thus we have tentatively classified about 50% of the unclassified missense variants observed during clinical testing of BRCA1. Discussion: An internal test of the analysis is consistent with our classification of the variants designated probably deleterious; however, we must stress that this classification is tentative and does not have sufficient independent confirmation to serve as a clinically applicable stand alone method.