Editorial: BRCA1 and BRCA2 gene mutations screening in
sporadic breast cancer patients in Kazakhstan
Rachel C. Jankowitz1, Kelly Z.
1University of Pittsburgh Cancer Institute, UPMC
Magee Women's Cancer Program;
2UPMC Center for Medical Genetics
While the majority of breast cancer cases are sporadic, up to 30% have
been described as familial. Hereditary breast cancer, accounting for
approximately 10% of breast cancer cases, has classically been
associated with highly penetrant gene mutations that are highly likely
to cause cancer, vertical transmission, autosomal dominant inheritance
pattern, association with other cancers, and early age of onset.1-5
contrast, these characteristics are often not exhibited in familial
breast cancers. Therefore, although familial breast cancers occur more
in an individual family than in the general population, they are
thought to be due to a complex interaction between lower penetrance
genes and environmental factors and/or random intra-familial sporadic
In 1994, inherited mutations in BRCA1 and BRCA2 genes that encode for
tumor suppressor proteins were linked to hereditary breast and ovarian
cancer.6,7 Since this groundbreaking scientific
discovery, much has
been learned about genetic risk of breast cancer (such as newer
detection techniques with improved sensitivity to detect BRCA1 and
BRCA2 large genomic rearrangements);8 however,
questions remain unanswered. The prevalence of known deleterious BRCA1
and BRCA2 gene mutations is approximately 1 in 400 individuals.9
variable penetrance, the probability of cancer development varies
amongst BRCA mutation carriers, (even amongst carriers in families with
the same mutation),10 but in general, BRCA
deleterious mutations confer
a 45-84% lifetime risk for breast cancer.11 It
is, therefore, not
surprising that known deleterious BRCA mutations are variable across
different ethnic and geographic populations. Moreover, founder
mutations have been identified within Ashkenzi Jewish, Icelandic, and
When discussing BRCA1 and BRCA2 sequence variants, the terminology can
be difficult to discern. Variations that confer increased cancer risk
are termed “deleterious mutations,” but a number of other changes in
BRCA1 and BRCA2 are rapidly emerging, the significance of which are
less clear. It is important, therefore, to use consistent language when
discussing such findings. Mutations and polymorphisms are both sequence
variants. The term “mutation” signifies any rare deviation in the DNA
sequence of a gene from the normal wild type. Polymorphisms, on the
other hand, are common variations in DNA that are generally considered
to occur with a frequency greater than 1%.12 If
a polymorphism is known
to be disease-causing, then it will typically be referred to as a
deleterious mutation, although most, but not all, deleterious mutations
are seen at a lower frequency in the population. Polymorphisms include,
but are not limited to: single nucleotide polymorphisms (SNPs),
insertions, deletions, or repeated sequences. SNPs are the most common
type of polymorphism accounting for approximately 90% of all human
genetic variation.13 Most SNPs are benign or
neutral polymorphisms with
no known clinical impact; however, it is thought that some may provide
useful clinical information, such as likelihood of developing disease,
response to disease, and perhaps implications for treatment.14
Polymorphisms and mutations can be further classified as synonymous or
non-synonymous based on their impact on the resulting amino acid. A
synonymous substitution results in a codon that does not lead to a
change in the coded amino acid, whereas non-synonymous substitutions,
such as missense mutations, do result in an amino acid change. Lastly,
variants of uncertain significance (VUS) are novel DNA changes with
unknown effects on protein function and disease risk. Pending further
investigation, an identified VUS could be reclassified as a deleterious
mutation or a polymorphism of no clinical significance in the future.15
In the current publication, Akilzhanova and colleagues examine the role
of BRCA1 and 2 mutations in Kazakhstan women with sporadic breast
cancer. They studied genomic DNA from 156 sporadic breast cancer cases
(defined as women without family history of affected first- or second-
degree relatives with breast and/or ovarian cancer) and 112 controls
(matched on age and ethnicity) from two different areas in Kazakhstan.
Ultimately, mutational screening of BRCA1 and BRCA2 coding regions for
these patients and controls identified 22 distinct variants (16
missense mutations of unknown clinical significance and 6
polymorphisms). No deleterious BRCA1 or 2 mutations were identified.
There were significantly more variants in the Caucasians versus the
Asian breast cancer cases and more variants in the Asian versus the
Caucasian controls. They also found a number of women (79 of 156, 71%)
who carried 4-6 alterations. This makes these alterations in the BRCA
sequence much less likely to be deleterious, particularly if they were
the same sequence variants that they termed “likely neutral
polymorphisms,” (those that were expressed at a high frequency in both
cases and controls).
Models incorporating variables from cancer history of patients as well
as multiple other factors into logistic regression analyses potentially
have the ability to segregate uncertain BRCA1 and BRCA2 variants into
deleterious and non-deleterious categories.16-22
These models work best
when there are enough occurrences of a single variant amongst unrelated
families to help aid in its classification. We are still limited in
finding ways to classify variants that occur rarely in a specific
Several resources exist for obtaining information regarding previously
identified VUS and SNPs including: the SNP Consortium,24
database from the National Center for Biotechnology Information (NCBI),
the Breast Cancer Information Core (BIC)
and HGVbase (Human Genome
Variation Database), which is a human gene-based polymorphism database.
Due to the difficulty in screening the literature in order to determine
whether a specific variant of uncertain significance has been
classified, reporting variants to such large comprehensive databases of
BRCA1 and 2 genes is critically important. Additionally, there is an
ENIGMA consortium that has been established to evaluate the
significance of uncertain variants in high-risk breast cancer genes.
The success of this group can only be achieved by collecting genetic
and clinical information, functional assays, and mRNA expression and
Via computational approaches, functional assay data has been shown to
correlate well with pathogenicity of BRCA1 variants of uncertain
significance.25 A guide for functional analysis
of BRCA1 variants of
uncertain significance has recently been published.26
five-tiered classification scheme for DNA sequence variants and
correlation of clinical recommendation with probability that any given
alteration is deleterious has been developed based on the posterior
probability model, with Class 1 and 2 being not likely pathogenic,
class 3 remaining a true VUS, and Class 4 and 5 considered
pathogenic/deleterious for clinical purposes.27,28
As an example, the
authors of the current publication found a BRCA1 amino acid variant of
Pro871Leu, which is listed as Class 1, likely not pathogenic,28
is consistent with the fact that it was found in about half of their
total population, both in cases and controls.
In conclusion, despite major advances in our BRCA testing, in many
instances we are still in a very elementary stage in applying such
information clinically toward the care of patients. It is only through
collaboration that the rapidly developing field of molecular genetics
will lead to advances in patient care.
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