BACKGROUND: BRCA1 and BRCA2 germline mutations predispose heterozygous carriers 
to hereditary breast/ovarian cancer. However, unclassified variants (UVs) 
(variants with unknown clinical significance) and missense polymorphisms in 
BRCA1 and BRCA2 genes pose a problem in genetic counseling, as their impact on 
risk of breast and ovarian cancer is still unclear. The objective of our study 
was to identify UVs and missense polymorphisms in Algerian breast/ovarian cancer 
patients and relatives tested previously for BRCA1 and BRCA2 genes germline 
mutations analysis.
METHODS: We analyzed 101 DNA samples from 79 breast/ovarian cancer families. The 
approach used is based on BRCA1 and BRCA2 sequence variants screening by SSCP or 
High-Resolution Melting (HRM) curve analysis followed by direct sequencing. In 
silico analyses have been performed using different bioinformatics programs to 
individualize genetics variations that can disrupt the BRCA1 and BRCA2 genes 
function.
RESULTS: Among 80 UVs and polymorphisms detected in BRCA1/2 genes (33 BRCA1 and 
47 BRCA2), 31 were new UVs (10 BRCA1 and 21 BRCA2), 7 were rare UVs (4 BRCA1 and 
3 BRCA2) and 42 were polymorphic variants (19 BRCA1 and 23 BRCA2). Moreover, 8 
new missense UVs identified in this study: two BRCA1 (c.4066C>A/p.Gln1356Lys, 
c.4901G>T/p.Arg1634Met) located respectively in exons 11 and 16, and six BRCA2 
(c.1099G>A/p.Asp367Asn, c.2636C>A/p.Ser879Tyr, c.3868T>A/p.Cys1290Ser, 
c.5428G>T/p.Val1810Phe, c.6346C>G/p.His2116Asp and c.9256G>A/p.Gly3086Arg) 
located respectively in exons 10, 11 and 24, show a damaging PSIC score yielded 
by PolyPhen2 program and could be pathogenic. In addition, 5 new BRCA} missense 
UVs out of six that were found to be damaging by PolyPhen2 program, also were 
deleterious according to SIFT program. The rare BRCA1 UV c.5332G>A/p.Asp1778Asn 
was found here for the first time in co-occurrence in trans with the deleterious 
BRCA1 mutation c.798_799delTT/p.Ser267LysfsX19 in young breast cancer patient. 
Moreover, 10 new identified intronic variants with unknown clinical significance 
(3 BRCA1 and 7 BRCA2) in the present study, could be considered as benign, 
because GeneSplicer, SpliceSiteFinder and MaxEntScan prediction programs show no 
splice site alteration for these variants. Several missense polymorphisms of 
BRCA1 c.2612C>T/p.Pro871Leu, c.3548A>G/p.Lys1183Arg, c.4837A>G/p.Ser1613Gly and 
BRCA2 c.865A>C/p.Asn289His, c.1114A>C/p.Asn372His, c.2971A>G/p.Asn991Asp, 
c.7150C>A/p.Gly2384Lys have been identified with high frequency in patients who 
were tested negative for BRCA1 and BRCA2 mutations. These missense polymorphisms 
could have a role as susceptibility breast cancer markers in Algerian 
breast/ovarian cancer families where pathological BRCA1 and BRCA2 mutations were 
not present.
CONCLUSIONS: For the first time, UVs and missense polymorphisms in BRCA1 and 
BRCA2 genes have been identified in Algerian breast/ovarian cancer families. 
Evaluation of breast/ovarian cancer risk induced by the eight new missense UVs 
and common polymorphisms detected in our present work is on going in a larger 
study.