BRCA1 R1699Q variant displaying ambiguous functional abrogation confers intermediate breast and ovarian cancer risk.
BACKGROUND
Clinical classification of rare sequence changes identified in the breast cancer susceptibility genes BRCA1 and BRCA2 is essential for appropriate genetic counselling of individuals carrying these variants. We previously showed that variant BRCA1 c.5096G>A p.Arg1699Gln in the BRCA1 transcriptional transactivation domain demonstrated equivocal results from a series of functional assays, and proposed that this variant may confer low to moderate risk of cancer.


METHODS
Measures of genetic risk (report of family history, segregation) were assessed for 68 BRCA1 c.5096G>A p.Arg1699Gln (R1699Q) families recruited through family cancer clinics, comparing results with 34 families carrying the previously classified pathogenic BRCA1 c.5095C>T p.Arg1699Trp (R1699W) mutation at the same residue, and to 243 breast cancer families with no BRCA1 pathogenic mutation (BRCA-X).


RESULTS
Comparison of BRCA1 carrier prediction scores of probands using the BOADICEA risk prediction tool revealed that BRCA1 c.5096G>A p.Arg1699Gln variant carriers had family histories that were less 'BRCA1-like' than BRCA1 c.5095C>T p.Arg1699Trp mutation carriers (p<0.00001), but more 'BRCA1-like' than BRCA-X families (p=0.0004). Further, modified segregation analysis of the subset of 30 families with additional genotyping showed that BRCA1 c.5096G >A p.Arg1699Gln had reduced penetrance compared with the average truncating BRCA1 mutation penetrance (p=0.0002), with estimated cumulative risks to age 70 of breast or ovarian cancer of 24%.


CONCLUSIONS
Our results provide substantial evidence that the BRCA1 c.5096G>A p.Arg1699Gln (R1699Q) variant, demonstrating ambiguous functional deficiency across multiple assays, is associated with intermediate risk of breast and ovarian cancer, highlighting challenges for risk modelling and clinical management of patients of this and other potential moderate-risk variants.
Division of Genetics and Population Health, Queensland Institute of Medical Research, Brisbane, Queensland, Australia. Amanda.Spurdle@qimr.edu.au
Amanda B
AB
Spurdle
Phillip J
PJ
Whiley
Bryony
B
Thompson
Bingjian
B
Feng
Sue
S
Healey
Melissa A
MA
Brown
Christopher
C
Pettigrew
Christi J
CJ
Van Asperen
Margreet G E M
MG
Ausems
Anna A
AA
Kattentidt-Mouravieva
Ans M W
AM
van den Ouweland
Annika
A
Lindblom
Maritta H
MH
Pigg
Rita K
RK
Schmutzler
Christoph
C
Engel
Alfons
A
Meindl
Sandrine
S
Caputo
Olga M
OM
Sinilnikova
Rosette
R
Lidereau
Fergus J
FJ
Couch
Lucia
L
Guidugli
Thomas van Overeem
Tv
Hansen
Mads
M
Thomassen
Diana M
DM
Eccles
Kathy
K
Tucker
Javier
J
Benitez
Susan M
SM
Domchek
Amanda E
AE
Toland
Elizabeth J
EJ
Van Rensburg
Barbara
B
Wappenschmidt
Åke
Å
Borg
Maaike P G
MP
Vreeswijk
David E
DE
Goldgar
D000368:Aged; D019313:BRCA1 Protein / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D060005:Genotyping Techniques; D057809:HEK293 Cells; D006801:Humans; D016013:Likelihood Functions; D009154:Mutation; D010051:Ovarian Neoplasms / Q000235:genetics*; D010375:Pedigree; D019683:Penetrance; D011237:Predictive Value of Tests; D012307:Risk Factors; D015533:Transcriptional Activation
D019313:BRCA1 Protein; C492913:BRCA1 protein, human