Genetic and histopathologic evaluation of BRCA1 and BRCA2 DNA sequence variants of unknown clinical significance.
Classification of rare missense variants as neutral or disease causing is a challenge and has important implications for genetic counseling. A multifactorial likelihood model for classification of unclassified variants in BRCA1 and BRCA2 has previously been developed, which uses data on co-occurrence of the unclassified variant with pathogenic mutations in the same gene, cosegregation of the unclassified variant with affected status, and Grantham analysis of the fit between the missense substitution and the evolutionary range of variation observed at its position in the protein. We have further developed this model to take into account relevant features of BRCA1- and BRCA2-associated tumors, such as the characteristic histopathology and immunochemical profiles associated with pathogenic mutations in BRCA1, and the fact that approximately 80% of tumors from BRCA1 and BRCA2 carriers undergo inactivation of the wild-type allele by loss of heterozygosity. We examined 10 BRCA1 and 15 BRCA2 unclassified variants identified in Australian, multiple-case breast cancer families. By a combination of genetic, in silico, and histopathologic analyses, we were able to classify one BRCA1 variant as pathogenic and six BRCA1 and seven BRCA2 variants as neutral. Five of these neutral variants were also found in at least 1 of 180 healthy controls, suggesting that screening a large number of appropriate controls might be a useful adjunct to other methods for evaluation of unclassified variants.
Queensland Institute of Medical Research, Brisbane, Australia.
Georgia
G
Chenevix-Trench
Sue
S
Healey
Sunil
S
Lakhani
Paul
P
Waring
Margaret
M
Cummings
Ross
R
Brinkworth
Amie M
AM
Deffenbaugh
Lynn Anne
LA
Burbidge
Dmitry
D
Pruss
Thad
T
Judkins
Tom
T
Scholl
Anna
A
Bekessy
Anna
A
Marsh
Paul
P
Lovelock
Ming
M
Wong
Andrea
A
Tesoriero
Helene
H
Renard
Melissa
M
Southey
John L
JL
Hopper
Koulis
K
Yannoukakos
Melissa
M
Brown
Douglas
D
Easton
Sean V
SV
Tavtigian
David
D
Goldgar
Amanda B
AB
Spurdle
D000483:Alleles; D001483:Base Sequence; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology*; D004273:DNA, Neoplasm / Q000235:genetics*; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D006801:Humans; D007150:Immunohistochemistry; D019656:Loss of Heterozygosity; D008875:Middle Aged; D008957:Models, Genetic; D009154:Mutation; D020125:Mutation, Missense
D004273:DNA, Neoplasm