Understanding the genetic epidemiology of hereditary breast cancer in India using whole genome data from 1029 healthy individuals.

Breast cancer is the most highly reported cancer in India. Genetic testing could help tackle the increasing cancer burden by enabling carriers obtain early diagnosis through increased surveillance, and help guide treatment. However, accurate interpretation of variant pathogenicity must be established in a population-specific manner to ensure effective use of genetic testing. Here we query IndiGen data obtained from sequencing 1029 Indian individuals, and perform variant classification of all reported BRCA variants using gold-standard ACMG & AMP guidelines to establish disease epidemiology. To address the high number of VUS variants thus obtained, we further utilize the brca-NOVUS ML tool to obtain pathogenicity predictions in a manner close to ACMG guidelines at scale. Through the manual application of ACMG & AMP guidelines, we determined the genetic prevalence to be the following: 1 in 342 carriers of BRCA1, and 1 in 256 carriers of BRCA2 pathogenic/likely pathogenic variants bear a significant lifetime risk of developing breast / ovarian cancer in India. The high population prevalence and unique variant landscape emphasizes a need for population-scale studies of causative variants to enable effective screening. We advise cautious clinical interpretation, given incomplete penetrance and other complex factors that result in cancer disease. To the best of our knowledge, this is the first and most comprehensive population-scale genetic epidemiological study of BRCA-linked breast cancer variants reported from India.