Patients with an unclassified genetic variant in the BRCA1 or BRCA2 genes show different clinical features from those with a mutation.
OBJECTIVE
To obtain and compare the probabilities of finding a mutation in the BRCA1 or BRCA2 genes, the clinical features, and the family history among patients with an unclassified variant (UV) and those with a pathogenic mutation.


METHODS
The study included 70 patients: 24 with a UV (BRCA1, n = 4; BRCA2, n = 19; both, n = 1), and 46 with a mutation (BRCA1, n = 32; BRCA2, n = 14). Two of the UVs were novel variants; the rest had been reported previously as UVs. Probabilities of finding a mutation were retrospectively obtained using BRCAPRO and Myriad II programs.


RESULTS
The probability to detect a mutation was significantly lower in the group of patients with a UV than in those with a mutation (BRCAPRO [mean +/- standard deviation], 0.297 +/- 0.312 v 0.627 +/- 0.315, P = .001; and Myriad II, 0.124 +/- 0.090 v 0.283 +/- 0.176, P = .001, respectively). Independent predictive factors of finding either a UV or a mutation were number of affected relatives (2.9 +/- 1.4 v 4.0 +/- 1.9; P = .039) and number of tumors among relatives (3.3 +/- 1.4 v 4.4 +/- 1.8; P = .031), respectively.


CONCLUSIONS
The combined data about the predictive models show significant differences between both groups. Individual probabilities can be regarded as a help to guide the clinical management of patients with a UV in those genes. However, a definitive conclusion about the pathogenicity of a UV can not be obtained from the clinical features alone, but only in combination with biochemical and epidemiologic data.
Gómez-García
Encarna B
EB
Department of Clinical Genetics, University Hospital Maastricht, PO Box 5800, 6202 AZ Maastricht, The Netherlands. Encarna.Gomezgarcia@gen.unimaas.nl
Ambergen
Ton
T
Blok
Marinus J
MJ
van den Wijngaard
Arthur
A
D000328:Adult; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology*; D004252:DNA Mutational Analysis; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D008487:Medical History Taking; D008875:Middle Aged; D008962:Models, Theoretical; D010375:Pedigree; D011379:Prognosis; D012189:Retrospective Studies