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Online mutation report
Loss of five amino acids in BRCA2 is associated with ovarian cancer
  1. S L Martinez1,
  2. J Herzog1,
  3. J N Weitzel1,2
  1. 1Department of Clinical Cancer Genetics, Beckman Research Institute
  2. 2City of Hope (COH) Comprehensive Cancer Center, Duarte, CA, USA
  1. Correspondence to:
 Dr J N Weitzel
 Director, Department of Clinical Cancer Genetics, City of Hope Cancer Center, 1500 E Duarte Road, Duarte, CA 91010, USA; jweitzelcoh.org

https://doi.org/10.1136/jmg.2003.010827

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    Hereditary breast and ovarian cancer (HBOC) syndrome is characterised by an early age of onset and an autosomal dominant pattern of inheritance. Mutations in BRCA1 or BRCA2 account for the majority of families with HBOC, with carriers bearing a lifetime risk of approximately 50–80% for breast cancer and 15–45% for ovarian cancer.1,2 Most deleterious mutations are small insertions/deletions, nonsense mutations, or splice site mutations that result in a frame shift and/or premature protein truncation. However, minor alterations such as missense mutations or small in frame insertions/deletions in the coding regions of BRCA1 and BRCA2 are often the only change detected. These present a clinical dilemma in cancer risk counselling because of their classification as variants of unknown significance (VUS), which are essentially uninformative findings.3

    A number of analytical strategies exist to elucidate the significance of a VUS. If the variant has been reported previously, the commercial vendor of the gene test provides ancillary data about the VUS, such as the number of observations, predominant racial or ethnic origin, whether seen concurrently with a known deleterious mutation, and whether the VUS tracks with disease in families where such testing is possible. In addition, given the presumed tumour suppressor function of the BRCA proteins, it has been suggested that somatic allelic deletion of the wild type allele in a tumour, as detected by loss of heterozygosity (LOH) analysis, can provide evidence for the deleterious nature of the respective germline mutations.4 Finally, the degree of evolutionary conservation of the amino acid sequence and the presence of functional domains in a given region of the protein can be considered circumstantial evidence for the importance of the amino acids encompassing that domain.5

    BRCA gene sequencing (Myriad Genetic Laboratories Inc, Salt Lake City, UT, USA) of a 50 year old ovarian …

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