Marginal Contribution of Pathogenic Germline Variants to Pakistani Early-Onset and Familial Breast/Ovarian Cancer Patients.

INTRODUCTION

has been reported as a breast cancer (BC) and ovarian cancer (OC) predisposition gene, particularly among Caucasian populations. We studied the prevalence of variants in Pakistani BC/OC patients.

MATERIALS AND METHODS

In total, 371 young or familial BC/OC patients were thoroughly analyzed for sequence variants using denaturing high-performance liquid chromatography pursued by DNA sequencing of differentially eluted amplicons. We also assessed the pathogenic effects of novel variants using in-silico algorithms. All detected variants were investigated in 400 unaffected controls.

RESULTS

No pathogenic variant was detected. However, we identified nine unique heterozygous variants. Of these, two missense variants (p.Pro10Leu and p.Ile311Asn) and one intronic variant (c.481-26_23delGTTC) were classified as in silico-predicted variants of uncertain significance, with a frequency of 0.8% (3/371). The p.Pro10Leu variant was detected in a 28-year-old female BC patient of Punjabi ethnic background, whose mother and maternal cousin had BCs at ages 53 and 40, respectively. This variant was also detected in 1/400 (0.25%) healthy controls, where the control subject's daughter had acute lymphoblastic leukemia. The p.Ile311Asn variant was identified in a female BC patient at age 29 of Punjabi ethnicity and in 1/400 (0.25%) healthy controls, where the control subject's daughter had Hodgkin's disease at age 14. A novel intronic variant, c.481-26_-23delGTTC, was found in a 30-year-old Punjabi female BC patient but not in 400 healthy controls.

CONCLUSION

No pathogenic variant was identified in the current study. Our study data suggested a negligible association of variants with BC/OC risk in Pakistani women.