Download Hereditary Breast and Ovarian Cancer

European Molecular Genetics Quality Network
EMQN
Supported by the Standards Measurement and Testing programme of the European Union *
* Contract no. SMT4-CT98-7515
Draft Best Practice Guidelines for Molecular Analysis of
Hereditary Breast and Ovarian Cancer
Mueller C1, Haworth A2.
1
Dept. of Human Genetics, University of Wuerzburg, Wuerzburg, Germany. 2South West Thames Regional
Molecular Genetics Laboratory, St Georges Hospital, London, United Kingdom.
Draft guidelines prepared by Clemens Mueller ([email protected]) and Andrea Haworth ([email protected] ) following
discussions at the EMQN workshop 26th May 2000 in Amsterdam, The Netherlands.
Disclaimer
These Guidelines are based, in most cases, on the reports drawn up
by the chairs of the disease-based workshops run by EMQN and the
CMGS. These workshops are generally convened to address specific
technical or interpretative problems identified by the QA scheme. In
many cases, the authors have gone to considerable trouble to collate
useful data and references to supplement their reports. However, the
Guidelines are not, and were never intended to be, a complete
primer or "how-to" guide for molecular genetic diagnosis of these
disorders. The information provided on these pages is intended for
chapter authors, QA committee members and other interested
persons. All the guidelines are at a draft stage, and must not be used
until formally published. Neither the Editor, the European Molecular
Genetics Quality Network, the Clinical Molecular Genetics Society,
the UK Molecular Genetics EQA Steering Committee nor the British
Society for Human Genetics assumes any responsibility for the
accuracy of, or for errors or omissions in, these Guidelines.
Nomenclature and gene ID
See table 1
.
Description of the disease
Breast cancer is the most common cancer in women
with a lifetime risk of up to 1 in 8 depending on the
ethnic background. Germline mutations in known and
unknown
susceptibility
genes
account
for
approximately 5-10% of affected women. To date two
major genes, BRCA1 and BRCA2 have been identified;
mutations in which are strongly associated with
predisposition to breast and ovarian cancer (Miki et al
1994, Wooster et al 1995, Tavtigian et al 1996). The
majority of mutations in both genes lead to protein
truncation and are inherited in an autosomal dominant
fashion.Mutations
in
BRCA1
accounts
for
approximately 50% of all hereditary breast cancer
cases, and in BRCA2 for about 35% (Ellison et al
1998). There are clearly additional genes involved that
may act as modifiers, for example the HRAS1
minisatellite (Phelan et al 1996). Other predisposing
genes of high to moderate penetrance are known to
lead to breast cancer or to syndromes involving breast
and/or ovarian cancer, e.g. BRCA3, p53, PTEN (Bishop
et al 1994, Easton et al 1997, ).
The risk of breast cancer in mutation carriers
has first been estimated from the study of selected
high-risk families. In this group of patients the risk of
developing breast cancer is greater than 80% by age
70. The risk figures given for ovarian cancer vary, with
40% overall risk by age 70 for BRCA1 and 27% for
BRCA2 carriers (Easton et al 1993, Narod et al 1995,
Ford et al 1998). At present, no penetrance estimates
are available for the general population. In a study on
an Ashkenazi Jewish population in the USA, unselected
for family history, a penetrance of the three common
Ashkenazi Jewish mutations of approximately 50-60%
has been observed (Struewing et al 1997).
There is also evidence that BRCA1 carriers
generally have a younger age of onset of breast cancer
than BRCA2 carriers (Ford et al 1998). There is little
evidence of clear genotype/phenotype correlations for
either gene. Most published reports are preliminary or
in contradiction to other studies.
There is some evidence that indicates that
mutation carriers are at increased risk of other
cancers, such as prostate cancer for male BRCA1
heterozygotes, and ocular melanoma, prostate and
pancreatic cancer for BRCA2 carriers.
Gene/Protein structure
BRCA1 consists of 22 coding exons, which are
transcribed into a 7.8 kb mRNA and encode a 1863
amino acid protein. Most of the exons are small,
comprising of 200 or so nucleotides, but one large
exon, exon 11, covers 61% of the coding region.
Another distinctive feature is that the genomic
sequence is rich in Alu repeats (40%).
BRCA2 consists of 26 coding exons, which are
transcribed into a 11-12 kb mRNA and encode a 3418
amino acid protein. Two large exons, 10 and 11,
account for 60% of the coding region; the remaining
exons are generally small.
The two proteins appear to participate in the
same pathways. The following roles have been
demonstrated for both genes; both are involved in the
maintenance of genomic stability by homologous
recombination and by transcription coupled and double
strand break repair (Scully et al 1997, Chen et al
1998). Both play a role in transcriptional regulation
(Scully et al 1997 and 4 other refs). BRCA1 is also
Guidelines for hereditary breast and ovarian cancer
© EMQN 2001
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Dr. Rob Elles (Co-ordinator) / Dr. Simon Patton (EMQN Administrator)
Regional Molecular Genetics Laboratory, St Mary’s Hospital, Hathersage Road, Manchester M13 0JH, United Kingdom
Tel: +44 161 276 6129/6741, Fax: +44 161 276 6606
Email: [email protected] / [email protected]
European Molecular Genetics Quality Network
EMQN
Supported by the Standards Measurement and Testing programme of the European Union *
* Contract no. SMT4-CT98-7515
involved in ubiquitination of proteins targeted for
cellular degradation (Lorrick et al 1999)
Ethnic Mutations
Among Ashkenazi Jews, three mutations have been
found at high prevalence: 185delAG and 5382insC in
BRCA1, and 6174delT in BRCA2. Individuals of known
Jewish ancestry should be screened for all three
mutations. This also applies to those without known
Jewish ancestry in whom one of these mutations has
previously been identified.
Other founder mutations have been described
in several populations and it may be worthwhile
targeting these common mutations in a patient of
relevant origin before initiating more extensive
mutation analysis.
Selection Criteria and Referrals
Throughout Europe referrals are accepted from several
types of clinicians, mainly Clinical Geneticists,
Oncologists and Obstetricians. The acceptance of
referrals is subject to local practices.
The mutation detection rate is to a large
degree, dependent upon the prior risk of the individual
patient. It is extremely useful if this risk, which should
be assessed by the referring clinician, is indicated on
the referral form along with a copy of the pedigree.
Mutation screening can be carried out on
either affected individuals, or unaffected individuals
with a very strong family history of breast/ovarian
cancer. The type of patient accepted for mutation
screening is dependent upon local guidelines.
Consent should be obtained from all patients
prior to storage or analysis of their sample. The tests
carried out upon the sample should be within the remit
of the referral. It is the responsibility of clinical
colleagues who are in personal contact with the patient
to obtain written informed consent before the sample
is taken. Consequently, it is acceptable for Molecular
Genetics laboratories to assume that written informed
consent has been obtained if the referral is from an
competent source.
Strategies
Testing should be carried out on the following category
of patients using genomic DNA/cDNA
ƒ Mutation screening in affected individuals.
ƒ Mutation screening in unaffected individuals with
strong family history
ƒ Mutation screening in unaffected individuals of
Jewish ancestry for the three common mutations
found in this population.
ƒ Predictive testing of at risk relatives.
ƒ Confirmation of the presence of a known mutation.
Points to consider
Occasionally, mutations in both BRCA1 and BRCA2
have been found in a single patient (one patient in
Scotland and by a laboratory participating in a UK
Breast and Ovarian Cancer Best Practice meeting unpublished findings). Therefore, it may be worth
screening both genes to completion even when one
mutation has already been identified, particularly if
there is a strong family history on both sides of the
pedigree.
Similarly, if a mutation is found in an
individual, it is advisable where possible, to determine
which side of the family it comes from prior to offering
predictive testing to the extended family.
As breast cancer is a common disease many
phenocopies can exist within families, therefore it may
be useful to carry out segregation analysis. If this is not
possible then it is wise to select the patient with the
lowest age of onset available.
Whole Gene Screen or Partial Gene Screen?
In an ideal world it would be preferable to have the
capacity to screen all exons of both genes and, in
addition, to perform dosage analysis on BRCA1.
However, this may only be practicable for a small
cohort of patients, i.e. those at very high risk of being
mutation carriers. Also local practices and funding may
prevent the full screen of both genes. Thus, it is
considered acceptable to carry out a limited screen,
which targets areas of the genes where common
mutations exist, typically exon 11, 2, 20 and 5 of
BRCA1 and exons 10 and 11 of BRCA2, as long as the
limits/extent of the analysis is indicated on any
subsequent reports.
Mutation Detection
Many mutation detection techniques are used and thus
it is not possible to establish a single recommended
technique. The technique used largely depends upon
local preferences and facilities.
DNA/RNA
The source material for testing varies; most
laboratories extract genomic DNA from blood samples,
whereas others also collect RNA from the same
patient. Generally RNA is extracted either to store for
future analysis and/or to confirm the effect of putative
splice mutations. Generally cDNA/RNA is not used as a
template for mutation screening, mainly due to
technical difficulties such asthe presence of spurious
bands and nonsense mediated decay of mRNA.
Linkage
Guidelines for hereditary breast and ovarian cancer
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Dr. Rob Elles (Co-ordinator) / Dr. Simon Patton (EMQN Administrator)
Regional Molecular Genetics Laboratory, St Mary’s Hospital, Hathersage Road, Manchester M13 0JH, United Kingdom
Tel: +44 161 276 6129/6741, Fax: +44 161 276 6606
Email: [email protected] / [email protected]
European Molecular Genetics Quality Network
EMQN
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* Contract no. SMT4-CT98-7515
Linkage analysis is not offered as a routine service and
is only available upon request.
Multiplex Heteroduplex analysis.
This technique is aimed at detection of small insertions
and deletions and not at the detection of single base
changes. It can be useful as an initial screen to look for
common mutations (Gayther et al 1996)
Fluorescent Conformational Sensitive Gel
Electrophoresis (F-CSGE)
Fluorescent multiplex analysis of fragments on an
Applied Biosystems (ABI) 377 DNA sequencer (or
equivalent) can be used for the detection of all types of
mutations by “automated” heteroduplex analysis
(Ganguly et al 1998). The use of various gel conditions
may be required to optimise the detection rate.
Although not widely used it is reported that the
sensitivity is approaching 100%. However, sensitivity is
probably lower at the ends of fragments. A possible
drawback is that the technique will pick up polymorphic
variants and variants of unknown pathological
significance as well as truncating mutations. Another
problem is that there is a lack of good interpretative
software for the anaylsis of results.
Single Stranded Conformational Polymorphism
(SSCP)
SSCP is an easy and low cost procedure which can be
automated on an ABI 377. Sensitivity is comparatively
low at 70-95% and several gel conditions may need to
be used to optimise detection in a single PCR
fragment/exon. The optimal fragment size is small at
200-250bp and multiplexing fragments can be difficult.
Reproducibility can also be a problem because of the
extreme sensitivity of SSCP's to temperature and other
gel conditions. As with F-CSGE this technique will pick
up all types of mutation/polymorphism.
Denaturing Gradient Gel Electrophoresis (DGGE)
As a heteroduplex based detection method, DGGE
relies upon heteroduplexes having differing melting
profiles under denaturing conditions. DGGE requires
special primers with a 5’ GC extension (GC clamp). This
method has a very high sensitivity once gel conditions
have been optimised and multiplexing allows for
reasonable throughput capacity. Drawbacks are that
the primers are relatively expensive and some special
equipment is required. There are programmes
available which will calculate the melting profiles of
fragments and aid experiment design. However, the
technique may be less reliable in GC rich regions. This
technique
will
detect
all
types
of
mutation/polymorphism.
Denaturing High Performance Liquid
Chromatography (DHPLC)
Like DGGE, this technique relies upon differential
denaturing profiles of heteroduplexes separated on an
HPLC column. Melting differences are exploited by the
application of a temperature profile specific for each
PCR fragment. The technique requires extensive
optimisation of conditions for each exon/PCR fragment
and a high initial investment for the machine. Although
the analyses are done sequentially, throughput is very
high and fully automated (96 well format). The running
cost per sample is very low and special/ labelled
primers are not required. Sensitivity also approaches
100 %. All kinds of sequence variants are detected,
though frequent polymorphisms may be recognised by
their characteristic elution profile.
Protein Truncation Test (PTT)
Unlike all other techniques, PTT aims at detecting only
those mutations which result in premature termination
of the protein product. This technique is particularly
suited to analysis of the large exons in BRCA1 and
BRCA2 and allows the use of genomic DNA as a test
source. The technique is relatively easy to perform and
doesn’t require special equipment. A possible technical
problem can occur when dividing the large exons into
overlapping PCR fragments, as care must be taken to
ensure that the primer overlap is large enough that
mutations near the end of one fragment, which may be
missed, are detectable in the next fragment. If exons
are amplified as a single fragment then it may be
necessary to run two gel conditions or to use a gradient
gel. Drawbacks are that PTT does not detect putative
missense mutations (not considered by many to be a
drawback) and also the use of radioactivity (typically
35S-methionine). A chemoluminescent kit for Western
blotting is now available.
Fluorescent Chemical Cleavage of Mismatch (FCCM)
This technique is based upon the cleavage of
chemically modified heteroduplex molecules by
piperidine. Heteroduplex PCR products are labelled by
incorporation of fluorescently labelled dUTP analogues
followed by treatment with hydroxylamine and
potassium permanganate. After chemical cleavage,
PCR products are electrophoresed on a denaturing gel
on the ABI 377 (or equivalent) and analysed by
Genescan. By multiplexing it is possible to analyse the
complete coding sequence of 6 patients for BRCA1, or
3 patients for BRCA2 using a 50 well ABI 377.
Advantages of the technique is that it can be
automated, sensitivity is reported to approach 100%
and large fragments up to 1kb can be analysed.
Disadvantages include the toxicity of hydroxylamine
Guidelines for hereditary breast and ovarian cancer
© EMQN 2001
3
Dr. Rob Elles (Co-ordinator) / Dr. Simon Patton (EMQN Administrator)
Regional Molecular Genetics Laboratory, St Mary’s Hospital, Hathersage Road, Manchester M13 0JH, United Kingdom
Tel: +44 161 276 6129/6741, Fax: +44 161 276 6606
Email: [email protected] / [email protected]
European Molecular Genetics Quality Network
EMQN
Supported by the Standards Measurement and Testing programme of the European Union *
* Contract no. SMT4-CT98-7515
and piperidine; the laborious nature of the analysis of
many small exons and the relatively high false positive
rate. Another drawback is that when multiple cleavage
events are expected in a single fragment, e.g. at 3
common polymorphisms in exon 11 of BRCA1, then it
is necessary to introduce a wildtype DNA to allow
heteroduplex formation and consistent cleavage.
Gene Dosage
Gross genomic rearrangements have been reported in
BRCA1, presumably due to the presence of a high
number of Alu repeats within the genomic sequence of
this gene. Detection of such rearrangements has been
reported using Southern blot analysis, RT-PCR analysis,
fluorescent
quantitative
PCR
and
Multiplex
Amplification of HYB. So far, rearrangements have
been reported in exon 1-2, 8-13, 13-16, 15, 17 and
27of BRCA1. No such rearrangements have been
reported in BRCA2 to date. Southern blot analysis is
slow, has low sensitivity (especially for duplications),
requires large amounts of DNA and frequently uses
high energy radioactivity. RT-PCR is technically
demanding and the sensitivity is affected by technical
problems and decay of mutant mRNAs. Quantitative
fluorescent PCR analysis is technically challenging but
has been used with considerable success for both, the
dystrophin and the BRCA1 genes using labelled PCR
primers and incorporation of fluorescent dNTPs (Yau et
al 1996, Robinson et al 2000). The advantage of this
technique is that it is sensitive, can be automated and
has potential high throughput capacity. Disadvantages
include the cost of labelled primers and the time taken
to optimise the technique.
Sequencing
Direct sequencing of PCR fragments using dye primers
is often quoted as the gold standard with a reported
sensitivity of 100 %. It is possible to automate all steps
and to have very high throughput capacity. Practically
the sensitivity is often not as high as reported, with
labs using this technique reporting lower sensitivity due
to practical problems and insensitive analysis software.
Disadvantages include the laborious nature of the
analysis oflarge numbers of small exons, and the
expense. Dye terminators can be used instead of Dye
Primers, but this reduces the sensitivity of the
technique. As with most of the other techniques it will
identify all types of mutation/polymorphism, except
genomic rearrangements.
EMD
To be added.
Mutation Specific tests.
Mutation specific tests such as Allele Specific Oligo’s,
ARMS and restriction enzyme digests etc. can be useful
when looking for specific common mutations in a
patient cohort, e.g. the three common Ashkenazi
Jewish mutations.
Controls
Positive controls should be used on all analyses to
ensure that the correct fragment is being analysed and
that the technique used is working. For predictive
testing a close relative carrying the mutation should be
used if possible; if not, another sample containing the
relevant mutation should be used. It is advisable to
confirm the presence of a particular mutation in the
family prior to offering predictive testing.
Interpretation and reporting
What is a mutation?
For the interpretation of an observed sequence variant
it is essential to establish the causal role of the
variation in the pathogenesis of the disease. Given the
vast heterogeneity of sequence changes in both genes
this constitutes a major challenge which requires
extensive biological assays and/or family studies.
Usually, this is not offered as part of a routine
diagnostic service. Published data are available for a
limited number of (recurrent) mutations only. In the
absence of experimental evidence, the pathological
significance of an observed sequence change has to
rely on plausibility considerations.
The following mutation types have most likely
pathological consequences for the protein function:
•
•
•
•
Mutations which formally interfere with proper
protein synthesis [nonsense mutations (= stop
codons), frame shifting mutations,
Mutations which are likely to lead to altered
splicing of the mRNA (splice site mutations). This
may be checked by mRNA studies,
Other mutations with experimental proof
(published or own data) of their impairment of the
protein’s function.
Sequence variants which have been shown to
strictly co-segregate with the disease in several
unrelated pedigrees and which are not found in a
large number of control samples.
All other sequence variants must be considered as
“unclassified” until functional evidence becomes
available.
Reports should be made to a Clinical
Geneticist or other acceptable source. The exact
content of the report is very much dependant on the
extent of the genetic knowledge of the referring
Guidelines for hereditary breast and ovarian cancer
© EMQN 2001
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Dr. Rob Elles (Co-ordinator) / Dr. Simon Patton (EMQN Administrator)
Regional Molecular Genetics Laboratory, St Mary’s Hospital, Hathersage Road, Manchester M13 0JH, United Kingdom
Tel: +44 161 276 6129/6741, Fax: +44 161 276 6606
Email: [email protected] / [email protected]
European Molecular Genetics Quality Network
EMQN
Supported by the Standards Measurement and Testing programme of the European Union *
* Contract no. SMT4-CT98-7515
clinician. Many have specialised in cancer genetics and
should thus be aware of the full clinical spectrum of
each gene.
Reports should include a statement of which
genes were tested and why, the extent and the limits of
the analysis and the methods used (refer to the UK
Clinical Molecular Genetics Society (CMGS) guidelines
on reporting - http://www.emqn.org/reports.htm)
Positive result in an affected index case.
The report should state that this result is consistent
with affection status and that other family members
are at risk. It should also state that the mutation is
likely to be the cause of the breast/ovarian cancer in
the family. It is generally felt inappropriate at this time
to point out the increased risk of other cancers in
mutation carriers i.e. the increased risk of prostate
cancer in male BRCA1 heterozygotes. Also interim
reports on PTT or other positive results (such as a SSCP
band shift) should only be issued if absolutely
necessary, and reporting should wait until the
causative mutation has been characterised.
Negative result in an affected index case
The risk of a pathological mutation segregating in the
family has not been changed. This also applies to a
negative result for an unaffected individual with a
strong family history or tested for common ethnic
mutations.
No comment should be made regarding the
percentage of mutations excluded, as ascertainment is
incomplete, even when every exon has been screened
and RNA expression examined. As mentioned above it
is necessary to include details of the extent of the
analysis.
Predictive testing
There is a large amount of discussion on the type of
sample required for predictive testing for a known
mutation. The methods used at the moment include
the following:
•
•
•
•
A single test on a single sample
Two identical tests on the same sample
Two different tests on the same sample
One identical test carried out on duplicate blood
samples taken at the same time or on different
days.
It is likely that other variations also occur. Generally it
is felt that this must be left to local practice or local
legislation.
The report should state that the risk of breast/ovarian
cancer has been reduced to that of the general
population in females. In males the test result should
be reported and mentioned that the result has
implications for any of his offspring, in particular his
daughters.
Positive predictive test
The report should state that this results in a high
lifetime risk of breast/ovarian cancer. It is not felt
appropriate to mention other BRCA related cancers at
this time. It is advisable not to report a specific risk, as
there is potential bias in the calculated risk figures, as
families with very high incidence of cancer were used
in their calculation (Easton et al 1997). There is clear
evidence that familial factors may influence risk and
that risk may be different for those unselected for
family history.
Prenatal diagnosis
Prenatal diagnosis is to be carried out under the same
criteria as with every other late onset disease. It should
always be referred from a clinical geneticist after
extensive genetic counselling.
Testing of minors
As there is no evidence that any symptoms will
manifest in childhood the testing of minors is not
recommended. What constitutes a minor will however,
differ depending upon national considerations.
Unknown variants
As extensive mutation analyses become common
practice many rare sequence variants are being
discovered in both genes. A major challenge for the
near future will be in how to interpret these variants.
Some may be pathogenic with high/medium/low
penetrance and may act as modifying factors. Until
functional analyses are obtained and proven it is
prudent to report them as “variants of unknown
pathological significance”, for all but the most common
variants which have been shown to segregate with the
disease in large pedigrees.
Breast cancer Information Core (BIC)
Although considered to be a useful resource the data
submitted to the Breast Cancer Information Core is not
validated and therefore care should be taken when
referring to it. Also submission is not widespread from
the diagnostic community and therefore the mutations
presented will not truly represent the full mutational
spectrum of either gene for many populations.
Negative predictive test
Guidelines for hereditary breast and ovarian cancer
© EMQN 2001
5
Dr. Rob Elles (Co-ordinator) / Dr. Simon Patton (EMQN Administrator)
Regional Molecular Genetics Laboratory, St Mary’s Hospital, Hathersage Road, Manchester M13 0JH, United Kingdom
Tel: +44 161 276 6129/6741, Fax: +44 161 276 6606
Email: [email protected] / [email protected]
European Molecular Genetics Quality Network
EMQN
Supported by the Standards Measurement and Testing programme of the European Union *
* Contract no. SMT4-CT98-7515
Future Developments
Apart from the obvious development in mutation
screening technology there are also exciting
developments in diagnosis. In particular the potential
use of microarrays to look at gene expression within
tumours and the ability to tie that in with family history
information. Likewise the improved capacity of
pathologists to recognise BRCA1-like tumours in
patients may offer further valuable information to
clinicians in assessing risk within families.
•
•
•
•
•
•
References
•
•
•
•
•
•
•
Miki Y et al (1994) A stong candidate for the breast and ovarian
cancer susceptibility gene BRCA1. Science 266:66-71
Wooster R et al (1995) Identification of the breast cancer
susceptibility gene BRCA2. Nature 378:789-792
Tavtigian S et al (1996) The complete BRCA2 gene and
mutations in chromosome 13q-linked kindreds. Nature Genet
12:333-337
Ellison et al (1998)
Phelan CM et al (1996a) Ovarian cancer risk in BRCA1 carriers
is modified by the HRAS1 variable number of tandem repeat
(VNTR) locus. Nature Genet 12:309-311
Phelan CM et al (1996b) Mutation analysis of the BRCA2 gene
in 49 site-specific breast cancer families. Nature Genet 13:120128
Bishop DT (1994) BRCA1, BRCA2, BRCA3 ... a myriad of breast
cancer genes. Eur J Cancer 30A:1738-1739
•
•
•
•
•
•
Easton D (1997) Breast cancer genes - what are the real risks.
Nature Genet 16:210-211
Easton et al (1993)
Narod SA et al (1995) Risk modifiers in carriers of BRCA1
mutations. Int J Cancer 64:6 394-398
Ford D et al (1998) Genetic heterogeneity and penetrance
analysis of the BRCA1 and BRCA2 genes in breast cancer
families. The Breast Cancer Linkage Consortium. Am J Hum
Genet 62:3 676-689
Struewing JP et al (1997) The risk of cancer associated with
specific mutations of BRCA1 and BRCA2 among Ashkenazi
Jews. N Engl J Med 336:20 1401-1408
Scully R et al (1997) Dynamic changes of BRCA1 subnuclear
location and phosphorylation state are initiated by DNA
damages. Cell 90:3 425-435
Chen et al (1998)
Lorrick et al (1999)
Gayther SA et al (1996) Rapid detection of regionally clustered
germ-line BRCA1 mutations by multiplex heteroduplex analysis
Am J Hum Genet. 58(3): 451-456
Ganguly T et al (1998) High throughput fluorescence-based
conformation-sensitive gel electrophoresis (F-CSGE) identifies
six unique BRCA2 mutations and an overall low incidence of
BRCA2 mutations in high-risk BRCA1-negative breast cancer
families Hum Genet 102:5 549-556
Yan et al (1996)
Robinson et al (2000)
Table 1. Nomenclature and gene ID
Gene
BRCA1
BRCA2
Useful links
OMIM#
113705
600185
Breast Cancer Information Core
Breast cancer linkage consortium
Human Gene Mutation Database
Myriad Genetics
Rosgen
Guidelines for hereditary breast and ovarian cancer
© EMQN 2001
6
Dr. Rob Elles (Co-ordinator) / Dr. Simon Patton (EMQN Administrator)
Regional Molecular Genetics Laboratory, St Mary’s Hospital, Hathersage Road, Manchester M13 0JH, United Kingdom
Tel: +44 161 276 6129/6741, Fax: +44 161 276 6606
Email: [email protected] / [email protected]