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Estimating risks for variants of unknown significance according to their predicted pathogenicity classes with application to BRCA1
Ist Teil von
Breast cancer research and treatment, 2014-02, Vol.144 (1), p.171-177
Ort / Verlag
Boston: Springer US
Erscheinungsjahr
2014
Link zum Volltext
Quelle
MEDLINE
Beschreibungen/Notizen
Sequence-based testing of disease-susceptibility genes has identified many variants of unknown significance (VUSs) whose pathogenicity is unknown at the time of their measurement. Female breast cancer cases aged 20–49 years at diagnosis and who have VUSs in
BRCA1
and no mutations in
BRCA2
have previously been identified through the population-based Los Angeles County Cancer Surveillance Program. These nominal
BRCA1
VUSs have been classified as “low,” “medium,” and “high” risk by four classification methods: Align-GVGD, Polyphen, Grantham matrix scores, and sequence conservation in mammalian species. Average hazard ratios (HRs) for classes of variants, i.e., the age-specific incidences of cancer for carriers of such variants divided by the population incidences, were estimated from the cancer family histories of first- and second-degree relatives of the index cases using modified segregation analysis. The study sample comprised 270 index cases and 4,543 of their relatives. There was weak evidence that the risk of breast cancer increases with the degree of sequence conservation (
P
= 0.03) and that missense variants at highly conserved sites are associated with a 5.6-fold (95 % confidence interval 1.4–22.2;
P
= 0.05) increased incidence of breast cancer. An upper bound of 2.3 is given for the average breast cancer HRs corresponding to variants classified as “low risk” by any of the four VUS classification methods. In summary, we have given a method to estimate cancer risks for groups of VUSs by combining existing classification methods with traditional penetrance analyses. This analysis suggests that classification methods for
BRCA1
variants based on sequence conservation might be useful in a clinical setting. We have shown in principle that our method can be used to classify VUSs into clinically useful risk categories, but our specific findings should not be put into clinical practice unless confirmed by larger studies.