A method to assess the clinical significance of unclassified variants in the BRCA1 and BRCA2 genes based on cancer family history.
BACKGROUND
Unclassified variants (UVs) in the BRCA1/BRCA2 genes are a frequent problem in counseling breast cancer and/or ovarian cancer families. Information about cancer family history is usually available, but has rarely been used to evaluate UVs. The aim of the present study was to identify which is the best combination of clinical parameters that can predict whether a UV is deleterious, to be used for the classification of UVs.


METHODS
We developed logistic regression models with the best combination of clinical features that distinguished a positive control of BRCA pathogenic variants (115 families) from a negative control population of BRCA variants initially classified as UVs and later considered neutral (38 families).


RESULTS
The models included a combination of BRCAPRO scores, Myriad scores, number of ovarian cancers in the family, the age at diagnosis, and the number of persons with ovarian tumors and/or breast tumors. The areas under the receiver operating characteristic curves were respectively 0.935 and 0.836 for the BRCA1 and BRCA2 models. For each model, the minimum receiver operating characteristic distance (respectively 90% and 78% specificity for BRCA1 and BRCA2) was chosen as the cutoff value to predict which UVs are deleterious from a study population of 12 UVs, present in 59 Dutch families. The p.S1655F, p.R1699W, and p.R1699Q variants in BRCA1 and the p.Y2660D, p.R2784Q, and p.R3052W variants in BRCA2 are classified as deleterious according to our models. The predictions of the p.L246V variant in BRCA1 and of the p.Y42C, p.E462G, p.R2888C, and p.R3052Q variants in BRCA2 are in agreement with published information of them being neutral. The p.R2784W variant in BRCA2 remains uncertain.


CONCLUSIONS
The present study shows that these developed models are useful to classify UVs in clinical genetic practice.
Gómez García
Encarna B
EB
Department of Clinical Genetics, University Hospital Maastricht, Maastricht, the Netherlands. Encarna.Gomezgarcia@gen.unimaas.nl
Oosterwijk
Jan C
JC
Timmermans
Maarten
M
van Asperen
Christi J
CJ
Hogervorst
Frans B L
FB
Hoogerbrugge
Nicoline
N
Oldenburg
Rogier
R
Verhoef
Senno
S
Dommering
Charlotte J
CJ
Ausems
Margreet G E M
MG
van Os
Theo A M
TA
van der Hout
Annemarie H
AH
Ligtenberg
Marjolijn
M
van den Ouweland
Ans
A
van der Luijt
Rob B
RB
Wijnen
Juul T
JT
Gille
Jan J P
JJ
Lindsey
Patrick J
PJ
Devilee
Peter
P
Blok
Marinus J
MJ
Vreeswijk
Maaike P G
MP
D000328:Adult; D019313:BRCA1 Protein / Q000235:genetics*; D024682:BRCA2 Protein / Q000235:genetics*; D001943:Breast Neoplasms / Q000097:blood / Q000175:diagnosis / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D008875:Middle Aged; D015233:Models, Statistical; D010051:Ovarian Neoplasms / Q000097:blood / Q000175:diagnosis / Q000235:genetics*; D011379:Prognosis; D012372:ROC Curve
D019313:BRCA1 Protein; D024682:BRCA2 Protein