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
