Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
J Med Genet
2004 Jul 01;417:492-507. doi: 10.1136/jmg.2003.015867.
Show Gene links
Show Anatomy links
Analysis of missense variation in human BRCA1 in the context of interspecific sequence variation.
Abkevich V
,
Zharkikh A
,
Deffenbaugh AM
,
Frank D
,
Chen Y
,
Shattuck D
,
Skolnick MH
,
Gutin A
,
Tavtigian SV
.
???displayArticle.abstract???
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.
Altschul,
Basic local alignment search tool.
1990, Pubmed
Altschul,
Basic local alignment search tool.
1990,
Pubmed
Aparicio,
Whole-genome shotgun assembly and analysis of the genome of Fugu rubripes.
2002,
Pubmed
Beaudet,
A suggested nomenclature for designating mutations.
1993,
Pubmed
Benner,
Amino acid substitution during functionally constrained divergent evolution of protein sequences.
1994,
Pubmed
Boguski,
Genomes and evolution.
1996,
Pubmed
Boyd,
A human BRCA1 gene knockout.
1995,
Pubmed
Brieger,
Transient mismatch repair gene transfection for functional analysis of genetic hMLH1 and hMSH2 variants.
2002,
Pubmed
Campbell,
BRCA1 polymorphisms.
1997,
Pubmed
Chasman,
Predicting the functional consequences of non-synonymous single nucleotide polymorphisms: structure-based assessment of amino acid variation.
2001,
Pubmed
Chen,
The nuclear localization sequences of the BRCA1 protein interact with the importin-alpha subunit of the nuclear transport signal receptor.
1996,
Pubmed
Deffenbaugh,
Characterization of common BRCA1 and BRCA2 variants.
2002,
Pubmed
Fairbrother,
Predictive identification of exonic splicing enhancers in human genes.
2002,
Pubmed
Ferrer-Costa,
Characterization of disease-associated single amino acid polymorphisms in terms of sequence and structure properties.
2002,
Pubmed
Fitch,
An improved method for determining codon variability in a gene and its application to the rate of fixation of mutations in evolution.
1970,
Pubmed
Flaman,
A simple p53 functional assay for screening cell lines, blood, and tumors.
1995,
Pubmed
Fleming,
Understanding missense mutations in the BRCA1 gene: an evolutionary approach.
2003,
Pubmed
Frank,
Sequence analysis of BRCA1 and BRCA2: correlation of mutations with family history and ovarian cancer risk.
1998,
Pubmed
Futreal,
BRCA1 mutations in primary breast and ovarian carcinomas.
1994,
Pubmed
Goodman,
Toward a phylogenetic classification of Primates based on DNA evidence complemented by fossil evidence.
1998,
Pubmed
Gowen,
Brca1 deficiency results in early embryonic lethality characterized by neuroepithelial abnormalities.
1996,
Pubmed
Grantham,
Amino acid difference formula to help explain protein evolution.
1974,
Pubmed
Hakem,
The tumor suppressor gene Brca1 is required for embryonic cellular proliferation in the mouse.
1996,
Pubmed
Hartge,
The prevalence of common BRCA1 and BRCA2 mutations among Ashkenazi Jews.
1999,
Pubmed
Hohenstein,
A targeted mouse Brca1 mutation removing the last BRCT repeat results in apoptosis and embryonic lethality at the headfold stage.
2001,
Pubmed
Hu,
Characterization of a novel trans-activation domain of BRCA1 that functions in concert with the BRCA1 C-terminal (BRCT) domain.
2000,
Pubmed
Huchon,
Rodent phylogeny and a timescale for the evolution of Glires: evidence from an extensive taxon sampling using three nuclear genes.
2002,
Pubmed
Ishioka,
Screening patients for heterozygous p53 mutations using a functional assay in yeast.
1993,
Pubmed
Joukov,
Functional communication between endogenous BRCA1 and its partner, BARD1, during Xenopus laevis development.
2001,
Pubmed
,
Xenbase
Jukes,
Deleterious mutations and neutral substitutions.
1971,
Pubmed
Koonin,
BRCA1 protein products ... Functional motifs..
1996,
Pubmed
Kuschel,
Apparent human BRCA1 knockout caused by mispriming during polymerase chain reaction: implications for genetic testing.
2001,
Pubmed
Liu,
Inactivation of the mouse Brca1 gene leads to failure in the morphogenesis of the egg cylinder in early postimplantation development.
1996,
Pubmed
Ludwig,
Tumorigenesis in mice carrying a truncating Brca1 mutation.
2001,
Pubmed
Ludwig,
Targeted mutations of breast cancer susceptibility gene homologs in mice: lethal phenotypes of Brca1, Brca2, Brca1/Brca2, Brca1/p53, and Brca2/p53 nullizygous embryos.
1997,
Pubmed
Markowitz,
Estimation and testing goodness-of-fit for some models of codon fixation variability.
1970,
Pubmed
Miller,
Understanding human disease mutations through the use of interspecific genetic variation.
2001,
Pubmed
Miyamoto,
Testing the covarion hypothesis of molecular evolution.
1995,
Pubmed
Murphy,
Resolution of the early placental mammal radiation using Bayesian phylogenetics.
2001,
Pubmed
Ng,
Accounting for human polymorphisms predicted to affect protein function.
2002,
Pubmed
Notredame,
T-Coffee: A novel method for fast and accurate multiple sequence alignment.
2000,
Pubmed
Nyström-Lahti,
Functional analysis of MLH1 mutations linked to hereditary nonpolyposis colon cancer.
2002,
Pubmed
Orelli,
Nine novel conserved motifs in BRCA1 identified by the chicken orthologue.
2001,
Pubmed
Panguluri,
BRCA1 mutations in African Americans.
1999,
Pubmed
Satagopan,
The lifetime risks of breast cancer in Ashkenazi Jewish carriers of BRCA1 and BRCA2 mutations.
2001,
Pubmed
Shattuck-Eidens,
BRCA1 sequence analysis in women at high risk for susceptibility mutations. Risk factor analysis and implications for genetic testing.
1997,
Pubmed
Szabo,
Human, canine and murine BRCA1 genes: sequence comparison among species.
1996,
Pubmed
Tang,
Prevalence of mutations in the BRCA1 gene among Chinese patients with breast cancer.
1999,
Pubmed
Thakur,
Localization of BRCA1 and a splice variant identifies the nuclear localization signal.
1997,
Pubmed
Vallon-Christersson,
Functional analysis of BRCA1 C-terminal missense mutations identified in breast and ovarian cancer families.
2001,
Pubmed
Vega,
The R71G BRCA1 is a founder Spanish mutation and leads to aberrant splicing of the transcript.
2001,
Pubmed
Zuckerkandl,
Molecules as documents of evolutionary history.
1965,
Pubmed
